Taxane derivatives and drugs containing the same

ABSTRACT

This invention relates to a taxane derivative represented by the following formula (1): wherein at least one of X and Y represents a group --CO--A--B in which A represents a single bond, an alkylenecarbonyl group or the like and B represents a substituted or unsubstituted piperidino group or the like, the other represents a tert-butoxycarbonyl group or the like, and Z represents a hydrogen atom or a triethylenesilyl group, and also to a drug containing the same. 
     This compound has high solubility in water and also has excellent antitumor activities.

TECHNICAL FIELD

This invention relates to taxane derivatives or salts thereof havingexcellent solubility in water, and also to drugs containing the same.

BACKGROUND ART

Taxol (registered trademark) (i) represented by the following formula(i): ##STR1## is a diterpenoid available by extraction from the bark ofthe Pacific yew tree, Taxus brevifolia, and was isolated and determinedin structure for the first time by Wall, et al. (J. Am. Chem. Soc., 93,2325, 1971). It has been reported to exhibit high efficacy againstovarian cancer and breast cancer (Ann. int. Med. 111, 273, 1989).

Formulation of Taxol into an injection however requires a specialsolvent, as it is a compound sparingly soluble in water. Taxol istherefore accompanied by problems in that the production of an injectionis difficult and side effects may be induced by a solvent.

A great deal of work has therefore been conducted in recent years with aview to developing a water-soluble derivative of Taxol (Nicolaou, etal., Nature 364, 464, 1993). Under the current circumstances, however,no derivatives have been found yet to be equipped with satisfactoryproperties.

Accordingly, an object of the present invention is to provide a noveltaxane derivative having improved water solubility and high antitumoractivities.

DISCLOSURE OF THE INVENTION

With the foregoing circumstances in view, the present inventors haveproceed with extensive research. As a result, it has been found that acompound represented by the below-described formula (1) and containingspecific substituent(s) introduced at the 3'-position and/or 10-positionof taxane (general name of the Taxol skeleton) has excellent antitumoractivities, has water solubility extremely higher than Taxol and ishence useful as a drug, leading to the completion of the presentinvention.

The present invention therefore provides a taxane derivative representedby the following formula (1): ##STR2## wherein at least one of X and Yrepresents a group --CO--A--B in which A represents a single bond, agroup --R--CO--, a group --R--OCO-- or a group --R--NHCO--, Rrepresenting a lower alkylene group or a phenylene group, B represents agroup ##STR3## in which R¹ represents a hydrogen atom, a substituted orunsubstituted alkyl group or an aralkyloxycarbonyl group, of a group##STR4## in which R² represents an amino group, a mono or di-alkylaminogroup, a piperidino group, a pyrrolidino group or a morpholino group, ora group ##STR5## in which R³ R⁵ and R⁶ each independently represent ahydrogen atom or a lower alkyl group and R⁴ represents a lower alkylenegroup, and the other represents a hydrogen atom, a lower alkanoyl group,a benzoyl group, an alkoxycarbonyl group or a trihalogenoalkoxycarbonylgroup; Z represents a hydrogen atom, a trialkylsilyl group or atrihalogenoalkoxycarbonyl group; Ac represents an acetyl group, Bzrepresents a benzoyl group, and Ph represents a phenyl group; or a saltthereof.

Further, the present invention also provides a drug comprising thetaxane derivative represented by the formula (1) or the salt thereof asan active ingredient.

Still further, the present invention also provides a drug compositioncomprising the taxane derivative represented by the formula (1) or thesalt thereof and a pharmaceutically acceptable carrier.

Moreover, the present invention also provides use of the taxanederivative represented by the formula (1) or the salt thereof as a drug.

In addition, the present invention also provides a method for thetreatment of a tumor, which comprises administering taxane derivativerepresented by the formula (1) or the salt thereof.

BEST MODES FOR CARRYING OUT THE INVENTION

The taxane derivative according to the present invention ischaracterized in that as is represented by the formula (1), one or bothof the 31-amino group and the 10-oxy group are a group --CO--A--B orgroups --CO--A--B. In each --CO--A--B, the lower alkylene grouprepresented by R in A may be a linear or branched alkylene group having1-6 carbon atoms, examples of which can include methylene, ethylene,trimethylene, propylene and tetramethylene, with methylene, ethylene andtrimethylene being particularly preferred. Particularly preferredexamples of the group represented by A can include a single bond, --C₂H₄ --CO--, --C₂ H₄ --NHCO--, CH₂ --OCO-- and --C₂ H₄ --OCO--.

The alkyl group represented by R¹ as a substituent on the piperazinogroup among the groups represented by B may be an alkyl group having1-10 carbon atoms, examples of which can include methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl,n-hexyl, n-heptyl, n-nonyl and n-decyl. Of these alkyl groups, thosehaving 1-6 carbon atoms, especially those having 1-3 carbon atoms arepreferred. Illustrative of substituent or substituents of the alkylgroup are monoalkylaminocarbonyl groups and dialkylaminocarbonyl groups.C₁₋₆ alkylaminocarbonyl groups can be mentioned as more preferredmonoalkylaminocarbonyl groups, and di-C₁₋₆ alkylaminocarbonyl groups canbe mentioned as more preferred dialkylaminocarbonyl groups. As thearalkyloxycarbonyl group, a phenyl-C₁₋₆ alkyloxycarbonyl group ispreferred, with a benzyloxycarbonyl group being particularly preferred.As examples of the alkyl moiety of the alkylamino group represented bythe substituent R² on the piperidino group, alkyl groups similar tothose described above as examples of the alkyl group represented by R¹can be mentioned, with methyl, ethyl, n-propyl and i-propyl beingpreferred. The lower alkyl groups as the substituents R³, R⁵ and R⁶ inthe group --N(R³)R⁴ --N(R⁵)R⁶ may be alkyl groups having 1-6 carbonatoms, examples of which can include methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, sec-butyl and tert-butyl, with methyl beingparticularly preferred. Further, the lower alkylene group represented byR⁴ may be a linear or branched alkylene group having 1-6 carbon atoms,examples of which can include methylene, ethylene, trimethylene,propylene and tetramethylene, with ethylene being particularlypreferred. Particularly preferred examples of the group represented by Bcan include piperidinopiperidino, pyrrolidinopiperidino,morpholinopiperidino, dialkylaminopiperidino and N-alkylpiperazino.

It is particularly preferred that this group --CO--A--B is bonded as oneof X and Y.

When only one of X and Y is the group --CO--A--B, the other is ahydrogen atom, a lower alkanoyl group, a benzoyl group, analkoxycarbonyl group or a trihalogenoalkoxycarbonyl group. Here, thelower alkanoyl group may be an alkanoyl group having 2-6 carbon atoms,preferred examples of which can include acetyl and propionyl. Thealkoxycarbonyl group may be a C₁₋₆ alkoxycarbonyl group, preferredexamples of which can include methoxycarbonyl and tert-butoxycarbonyl.Further, the trihalogenoalkoxycarbony group may be a trihalogeno-C₁₋₆alkoxycarbonyl group, preferred examples of which can include2,2,2-trichloroethoxycarbonyl. Particularly preferred examples of groupsrepresented by X and Y, other than --CO--A--B, can include, hydrogenatom, acetyl, 2,2,2-trichloroethoxycarbonyl, benzoyl andtert-butoxycarbonyl.

The group represented by Z is a hydrogen atom, a trialkylsilyl group, ora trihalogenoalkylcarbonyl group. Of these, a hydrogen atom, a tri(C₁₋₆alkyl)silyl group or trihalogeno(C₁₋₆ alkoxy)carbonyl group ispreferred, with hydrogen atom, triethylsilyl or2,2,2-trichloroethoxycarbonyl being particularly preferred.

Illustrative of the salt of the taxane derivative (1) according to thepresent invention are pharmacologically acceptable salts, for example,anion salts such as acid salts, hydroiodide, tartrate, acetate,methanesulfonate, maleate, succinate, glutarate, and salts with aminoacids such as arginine, lysine and alanine. Further, the taxanederivative or the salt thereof according to the present invention mayexist in the form of a hydrate. The hydrate is also embraced in thepresent invention.

The taxane derivative (1) or the salt thereof according to the presentinvention can be prepared, for example, in accordance with the followingreaction scheme (1) or reaction scheme (2).

<Reaction Scheme (1)> ##STR6## wherein A, B, Z, Ac, Bz and Ph have thesame meanings as defined above, Y¹ represents a hydrogen atom, a loweralkanoyl group, a benzoyl group, an alkoxycarbonyl group or atrihalogenoalkoxycarbonyl group, and Cbz represents a benzyloxycarbonylgroup.

Described specifically, a taxane derivative (1a) according to thepresent invention is obtained by (ii) providing 10-deacetylbaccatin III,a known compound, as a raw material, (iii) protecting its 7- and10-hydroxyl groups with suitable protecting groups, (iv)oxazolidinylating the 13-hydroxyl group, (v) subjecting theoxazolidinylated compound to ring opening, and then introducing awater-solubility-imparting B--A--CO group.

The protection of the 7- and 10-hydroxyl groups of 10-deacetylbaccatinIII can be carried out by reacting an alkanoyl halide, trialkylsilylhalide, trichloroethoxycarbonyl halide or the like with10-deacetylbaccatin III. The protecting groups may be selected asdesired from conventionally-known protecting groups for a hydroxylgroup, but triethylsilyl (TES), acetyl groups (Ac),trichloroethoxycarbonyl 1S groups or the like are preferred.

The 13-hydroxyl group is then oxazolidinylated to obtain the compound(iv). The oxazolidinylation may be conducted, for example, by reacting aderivative of oxazolidinecarboxylic acid, e.g.,N-benzyloxycarbonyl(Cbz)-2,2-dimethyl-4-phenyl-oxazolidinecarboxylicacid, DCC, dimethylaminopyridine (DMAP) or the like with the compound(iii).

Next, concerning the ring opening of the oxazolidine ring, the objectcan be achieved by treating the oxazolidinylated compound (iv) with anacid in a solvent such as ethanol, deprotecting (TES), and thenconducting catalytic reduction in the presence of palladium on charcoal.

The 3'-amino group of the resultant compound (v) is acylated by asuitable method, and the side chain (B--A--CO--) having a function toimpart water solubility, which features the present invention, is thenintroduced, whereby the taxane derivative (1a) according to the presentinvention is successfully prepared.

Examples of the acylating method can include a method making use of anacid derivative in the presence of a suitable base and a method makinguse of a condensing agent.

Illustrative of an acylating reagent usable for the above acylation areacid chlorides, acid anhydrides and acid esters, and derivativesequivalent to these acylating reagents.

As a specific method for introducing the group (B--A--CO--),4-dimethylaminopiperidinocarbonylation, for example, can be achieved byconducting treatment with 4-dimethylaminopiperidinocarbonyl chloride inthe presence of a suitable base (for example, n-butyl-lithium) whileusing a solvent such as THF.

<Reaction Scheme (2)> ##STR7## wherein A, B, Ac, Bz and Ph have the samemeanings as defined above, X¹ represents a group --CO--A--B, a loweralkanoyl group, a benzoyl group, an alkoxycarbonyl group and atrihalogenoalkoxycarbonyl group, R⁷ represents a hydrogen atom, analkoxycarbonyl group or an aralkyloxycarbonyl group, R⁸ and R⁹ eachindependently represent a hydrogen atom, an alkyl group, a halogenoalkylgroup or an alkoxyphenyl group with the proviso that R⁸ and R⁹ do notrepresent hydrogen atoms at the same time and, when one of R⁸ and R⁹ isa halogenoalkyl group or an alkoxyphenyl group, the other is a hydrogenatom, and Z' represents a trialkylsilyl group (TES) or an alkoxycarbonylgroup.

Described specifically, a target taxane derivative (1c) is obtained by(ii) providing lo-deacetylbaccatin III, a known compound, as a rawmaterial, (vi) protecting its 7-hydroxyl group with a trialkylsilylgroup or the like, (vii) acylating the resultant compound with a view tointroducing a water-solubility-imparting B--A--CO-- group into the10-hydroxyl group, whereby the water-solubility-imparting B--A--CO--group is introduced, (viii) oxazolidinylating the 13-hydroxyl group,subjecting the oxazolidinylated compound to ring opening to obtain thecompound (1b), and then introducing a water-solubility-impartingB--A--CO group or another acyl group.

The protection of the 7-hydroxyl group of 10-deacetylbaccatin III iscarried by a method known in the art. Specifically, it can be achievedby conducting treatment with a trialkylsilyl chloride or alkoxycarbonylchloride in pyridine. The protecting group may preferably be atrialkylsilyl group, with a tri(C₁₋₆ alkyl)silyl group being morepreferred and a triethylsilyl group being especially preferred.

The 10-hydroxyl group of the compound (vi) is then acylated, so that theside chain (B--A--CO--) having a function to impart water solubility isintroduced.

As a method for conducting the acylation, the acylation may be carriedout in a similar manner as in the above-described reaction scheme (1).

The 13-hydroxyl group is then oxazolidinylated to obtain the compound(vii). The oxazolidinylation may be conducted in a similar manner as inthe above-described reaction scheme (1).

The compound (vii) so obtained is treated with an acid optionally in asolvent such as ethanol, whereby the compound (vii) is deprotected(de-TES or the like), and catalytic reduction is then conducted in thepresence of palladium on charcoal to achieve ring opening of theoxazolidino ring, whereby the compound (1b) can be obtained.

The compound (1b) can be converted into the compound (1c) according tothe present invention by substituting its amino group with B--A--COO--,alkoxycarbonylating the amino group or protecting the amino group with abenzoyl group. Here, the alkoxycarbonyl may be C₁₋₆ alkoxycarbonyl, witht-butoxycarbonyl being Si: particularly preferred. Thet-butoxycarbonylation can be attained by conducting treatment, forexample, with t-butoxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine andtriethylamine or the like. The benzoyl protection can be achieved byreacting benzoic anhydride or the like.

The compound--which is employed in the preparation steps of the compound(1) according to the present invention and is represented by thefollowing formula (2): ##STR8## wherein A, B, Z, Ac and Bz have the samemeanings as defined above and E represents a hydrogen atom or a group:##STR9## wherein R⁷ represents a hydrogen atom, an alkoxycarbonyl groupor an aralkyloxycarbonyl group, R⁸ and R⁹ each independently represent ahydrogen atom, an alkyl group, a halogenoalkyl group or an alkoxyphenylgroup with the proviso that R⁸ and R⁹ do no represent hydrogen atoms atthe same time and, when one of R⁸ and R⁹ is a halogenoalkyl group or analkoxyphenyl group, the other is a hydrogen atom--is a novel compoundand is a compound useful as a synthesis intermediate for the compound(1).

The alkyl groups represented by R⁸ and R⁹ may be an alkyl group having1-10 carbon atoms, especially 1-6 carbon atoms, with methyl being morepreferred. Further, the halogenoalkyl group may preferably be ahalogeno(C₁₋₆ alkyl) group, with trichloromethyl being particularlypreferred. The alkoxyphenyl group may preferably be a C₁₋₆ alkoxyphenylgroup, with a 4-C₁₋₆ alkoxyphenyl group being more preferred, and4-methoxyphenyl being especially preferred.

The taxane derivative (1) according to the present invention wasconfirmed to have excellent antitumor activities in a test which wasconducted by using, as an index, growth inhibition effects against acell strain KB.

As the taxane derivative and the salt thereof according to the presentinvention have very high solubility in water (1,000-fold or highercompared with Taxol), they can be used as drugs such as injectionswithout using any special solvent. As drug preparations, injections suchas intravenous injections or intramuscular injections are preferred. Inaddition to such injections, they can also be formulated into liquidpreparations such as inhalations, syrups or emulsions; solidpreparations such as tablets, capsules or granules; or externalpreparations such ointments or suppositories.

These preparations may generally contain pharmacologically acceptablecarriers, such as dissolution aids, stabilizers, humectants,emulsifiers, absorption enhancers and surfactants, as needed.Illustrative of these carriers are injection-grade distilled water,Ringer's injection, glucose, sucrose syrup, gelatin, edible oil, cacaobutter, magnesium stearate, and talc.

The amount of the taxane derivative (1) contained in each of theabove-described respective drug preparation varies depending on theconditions of a patient to whom the drug preparation is administered,its preparation form and the like. In general, however, its amount perunit dosage form may desirably range from about 0.5 to 100 mg in thecase of injections, from about 5 to 1,000 mg in the case of oralpreparations, from about 5 to 1,000 mg in the case of suppositories.Further, the daily dosage of the drug having the above-described dosageforms varies depending on the condition, body weight, age, sex and thelike of each patient and cannot be determined in a wholesale manner.Nonetheless, the daily dosage may generally be about 0.1-50 mg/kg,preferably about 1-20 mg/kg per adult. It is preferred to administerthis dosage as a single dose or in divided dosage forms, two to fourtimes a day.

EXAMPLES

The present invention will next be described in further detail byExamples. It should however be borne in mind that the present inventionis not limited to them.

Example 1

10-O-(4-Dimethylaminopiperidinocarbonyl)-7-O-triethylsilyl-10-deacetylbaccatinIII (Compound 1)

1) Triphosgene (1.78 g, 6 mmol) was dissolved in benzene (120 ml),followed by the addition of a solution of 4-dimethylaminopiperidine(1.96 g, 15.3 mmol) in benzene and triethylamine (1.82 g, 18 mmol). Theresulting mixture was stirred overnight at room temperature. Chloroformwas added to the reaction mixture, and the resulting mixture was washedwith water. The organic layer was dried over anhydrous magnesiumsulfate, the solvent was distilled off under reduced pressure, and theresidue was then purified by chromatography on a silica gel(chloroform-acetone mixed solvent [1:2]), whereby4-dimethylaminopiperidinocarbonyl chloride (465 mg, 16%) was obtained.

¹ H-NMR (CDCl₃)δ: 1.49(2H,m), 1.86(2H,d,J=10 Hz), 2.27(6H,s),2.37(1H,m), 2.92(1H,t,J=11 Hz), 3.10(1H,t,J=13 Hz), 4.30(2H,d,J=13 Hz).

2) 7-O-Triethylsilyl-10-deacetylbaccatin III (135 mg, 0.20 mmol) wasdissolved in THF. The resulting solution was stirred for 15 minutes overan acetone bath of -40° C. and a solution (0.24 mmol) of n-butyl-lithiumin hexane was then added, followed by stirring for 30 minutes. Asolution of 4-dimethylaminopiperidinocarbonyl chloride (127 mg, 0.67mmol) in THF was to the thus-obtained solution, and the temperature wasraised from -40° C. to room temperature, at which the contents werestirred overnight. A saturated aqueous solution of ammonium chloride wasadded to the reaction mixture. The resulting mixture was stirred,followed by the addition of chloroform. The mixture so obtained waswashed with a saturated aqueous solution of sodium hydrogencarbonate.The organic layer was dried over anhydrous magnesium sulfate, thesolvent was distilled off under reduced pressure, and the residue waspurified by chromatography on a silica gel column (chloroform-methanolmixed solvent [9:1]), whereby the title compound (146 mg, 90%) wasobtained.

¹ H-NMR (CDCl₃)δ: 0.59(6H,m), 0.91(9H,t,J=8 Hz), 1.03(3H,s), 1.14(3H,s),1.60(3H,s), 2.20(3H,s), 2.27(3H,s), 1.41-2.30(8H,m), 2.38-3.05(9H,m),3.87(1H,d,J=7 Hz,C3-H), 4.13(1H,d,J=8 Hz,C20-H), 4.29(1H,d,J=9Hz,C20-H), 4.38(2H,br), 4.67(1H,dd,J=10,7 Hz,C7-H), 4.83(1H,br,C13-H),4.94(1H,d,J=8 Hz,C5-H), 5.61(1H,d,J=7 Hz,C2-H), 6.38(1H,s,C10-H),7.46(2H,t,J=8 Hz), 7.59(1H,t,J=7 Hz), 8.09(2H,d,J=7 Hz).

Example 2

13-O-(3-Benzyloxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarbonyl)-10-O-(4-dimethylaminopiperidinocarbonyl)-7-O-triethylsilyl-10-deacetylbaccatinIII (Compound 2)

The compound (146 mg, 0.18 mmol) of Example 1 was dissolved in toluene,followed by the addition of3-benzyloxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylic acid(160 mg, 0.45 mmol), DCC (93 mg, 0.45 mmol) and DMAP (2 mg). Theresulting mixture was stirred at room temperature for 20 hours. Thereaction mixture was filtered. After the filtrate was concentrated,chloroform was added to the residue. The thus-obtained mixture waswashed with a saturated aqueous solution of sodium hydrogencarbonate.The organic layer was dried over anhydrous magnesium sulfate, thesolvent was distilled off under reduced pressure, and the residue waspurified by chromatography on a silica gel column (chloroform-methanolmixed solvent [19:1]), whereby the title compound (207 mg, 100%) wasobtained.

¹ H-NMR (CDCl₃)δ: 0.56(6H,m), 0.90(9H,t,J=8 Hz), 1.17(6H,s), 1.65(3H,s),1.74(3H,s), 1.80(3H,s), 1.89(3H,s), 2.07(3H,s), 1.32-2.20(8H,m),2.27-3.05(8H,m), 3.77(1H,d,J=7 Hz,C3-H), 4.08(1H,d,J=8 Hz,C20-H),4.23(1H,d,J=9 Hz,C20-H), 4.30(2H,br), 4.43(1H,dd,J=10,7 Hz,C7-H),4.49(1H,d,J=6 Hz), 4.86(1H,d,J=8 Hz,C5-H), 4.81-5.18(2H,m), 5.21(1H,s),5.63(1H,d,J=8 Hz,C2-H), 6.21(1H,br,C13-H), 6.36(1H,s,C10-H),6.73(1H,br), 7.22-7.40(9H,m), 7.47(2H,t,J=7 Hz), 7.59(1H,t,J=7 Hz),8.02(2H,d,J=7 Hz).

Example 3

13-O-[3-(tert-Butoxycarbonylamino)-2-hydroxy-3-phenylpropionyl]-10-O-(4-dimethylaminopiperidinocarbonyl)-10-deacetylbaccatinIII (Compound 3)

The compound (106 mg, 0.092 mmol) of the compound of Example 2 wasdissolved in ethanol (5 ml), followed by the addition of 0.1 Nhydrochloric acid (10 ml). The resulting mixture was stirred at roomtemperature for 17 hours. The solvent was distilled off under reducedpressure, and chloroform was added to the residue. The thus-obtainedmixture was washed with a saturated aqueous solution of sodiumhydrogencarbonate. The organic layer was dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure.Methanol (10 ml), water (1 ml) and 10% palladium-charcoal (50 mg) wereadded to the residue, followed by stirring for 2 hours at roomtemperature and atmospheric pressure under a hydrogen gas atmosphere.The reaction mixture was filtered through a glass filter with Celitedistributed thereon. After the filtrate was concentrated, methylenechloride (10 ml) was added to the residue so that the residue wasdissolved. To the solution so obtained,S-tert-butoxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine (24 mg, 0.10mmol) and triethylamine (10 mg, 0.10 mmol) were added. The resultingmixture was stirred at room temperature for 3 days and further at 40° C.for 2 days.

Chloroform was added to the reaction mixture, and the resulting mixturewas washed with a saturated aqueous solution of sodiumhydrogencarbonate. The organic layer was dried over anhydrous magnesiumsulfate, the solvent was distilled off under reduced pressure, and theresidue was preliminarily purified by chromatography on a silica gelcolumn (chloroform-methanol mixed solvent [9:1]). Further purificationwas conducted by reverse-phase high-performance column chromatography(eluent: 10 mM potassium dihydrogen-phosphate-acetonitrile [1:1]),whereby the title compound (43 mg, 49%) was obtained.

¹ H-NMR (CDCl₃)δ: 1.05(3H,s), 1.20(3H,s), 1.27(9H,s), 1.64(3H,s),1.80(3H,s), 2.36(3H,s), 1.23-2.50(8H,m), 2.74(6H,s), 2.89(1H,br),3.12-3.43(2H,m), 3.38(1H,s), 3.71(1H,d,J=7 Hz,C3-H), 4.10(1H,d,J=8Hz,C20-H), 4.24(1H,d,J=8 Hz,C20-H), 4.22-4.43(3H,m), 4.56(1H,s,C2'-H),4.89(1H,d,J=10 Hz,C5-H), 5.23(1H,br), 5.28(1H,d,J=10 Hz,C3'-H),5.59(1H,d,J=7 Hz,C2-H), 6.18(1H,br,C13-H), 6.20(1H,s,C10-H), 7.31(5H,m),7.43(2H,t,J=8 Hz), 7.55(1H,t,J=7 Hz), 8.04(2H,d,J=7 Hz). SI-MS m/z: 962[M+H]⁺

Example 4

10-O-(4-Dipropylaminopiperidinocarbonyl)-7-O-triethylsilyl-10-deacetylbaccatinIII (Compound 4)

7-O-Triethylsilyl-10-deacetylbaccatin III (100 mg, 0.15 mmol) wasdissolved in tetrahydrofuran (5 ml), followed by the addition of a 1.6 Msolution of n-butyllithium in hexane (0.13 ml, 0.195 mmol) at -40° C.under an argon gas atmosphere. The resulting mixture was stirred for 1hour. Further, a solution of 4-dipropylaminopiperidinocarbonyl chloride(28 mg, 0.17 mmol) in tetrahydrofuran (1 ml) was added. Thethus-obtained mixture was stirred at -20° C. The temperature of themixture was then raised gradually to room temperature, at which themixture was stirred over-night. An aqueous solution of ammonium chloride(50 ml) was then added to the reaction mixture, and the resultingmixture was extracted with ethyl acetate. The organic layer was washedwith a saturated aqueous solution of sodium chloride, dried overanhydrous sodium sulfate, and then concentrated to dryness under reducedpressure. The residue was purified by chromatography on a silica gelcolumn (chloroform-methanol [96:4]). Eluted TLC single-spot fractionswere combined together and then concentrated to dryness under reducedpressure, whereby the title compound (63 mg, 50%) was obtained ascolorless crystals.

¹ H-NMR (CDCl₃)δ: 0.56-0.64(6H,m,Si--CH₂ X3), 0.87-0.95(15H,m,-MeX3 andpropyl-MeX2), 1.05(3H,s,C-16 or C17-Me), 1.18(3H,s,C16 or C-17-Me),1.44(3H,br-s), 1.60(3H,br-s), 1.68(3H,s,C19-Me), 1.75-1.89(2H,m),1.84-1.90(1H,m,C6-H), 2.25(3H,s,C18-Me), 2.25-2.30(2H,m,C14-H),2.28(3H,s,C4-OAc), 2.41(2H,s), 2.52(3H,m), 2.61-2.87(3H,m),3.90(1H,d,J=7 Hz,C3-H), 4.15(1H,d,J=8 Hz,C20-H), 4.27(1H,br-s),4.30(1H,d,J=9 Hz,C20-H), 4.47(1H,br-s), 4.49(1H,dd,J=7,11 Hz,C7-H),4.84(1H,m,C13-H), 4.96(1H,d,J=8 Hz,C5-H), 5.64(1H,d,J=7 Hz,C2-H),6.39(1H,s,C10-H), 7.46-7.49(2H,m,ArH), 7.58-7.62(1H,m,ArH),8.11(2H,d,J=7 Hz,ArH). SI-MS m/z: 869 [M+H]⁺

Example 5

10-O-(4-Dipropylaminopiperidinocarbonyl)-13-O-(4-phenyl-2-trichloromethyl-5-oxazolidinecarbonyl)-7-O-triethylsilyl-10-deacetylbaccatinIII (Compound 5)

The compound (22 mg, 0.025 mmol) of Example 4 and4-phenyl-2-trichloromethyl-5-oxazolidinecarboxylic acid (31 mg, 0.1mmol) were dissolved in toluene (5 ml), followed by the addition of DCC(23 mg, 0.11 mmol) and dimethylaminopyridine (1 mg). The resultingmixture was stirred at room temperature for 2 hours under an argon gasatmosphere. A precipitate in the reaction mixture was filtered off, anda saturated aqueous solution of sodium hydrogencarbonate was added tothe filtrate. The thus-obtained mixture was extracted with ethylacetate. The organic layer was washed with a saturated aqueous solutionof sodium chloride, dried over anhydrous sodium sulfate, and thenconcentrated to dryness under reduced pressure. The residue was purifiedby chromatography on a silica gel column (chloroform-methanol mixedsolvent (95:5)). Eluted TLC single-spot fractions were combined togetherand then concentrated to dryness under reduced pressure, whereby thetitle compound (20 mg, 70%) was obtained as colorless crystals.

¹ H-NMR (CDCl₃)δ: 0.57-0.61(6H,m,Si--CH₂ X3), 0.85-0.92(15H,m,-MeX3 andpropyl-MeX2), 1.21(6H,s,C16-Me and C17-Me), 1.37-1.87(9H,m),1.65(3H,s,C19-Me), 1.78(3H,s,C18-Me), 2.11(3H,s,C4-OAc),2.11-2.14(2H,m,C14-H), 2.38-3.00(8H,m), 3.27(1H,t,J=6 Hz,-NH--),3.77(1H,d,J=7 Hz,C3-H), 4.09(1H,d,J=8 Hz,C20-H), 4.23(1H,d,J=8Hz,C20-H), 4.26(1H,br-s), 4.42(1H,br-s), 4.45(1H,dd,J=7 Hz,10 Hz,C7-H),4.67-4.69(1H,m), 4.74-4.78(1H,m), 4.87(1H,d,J=8 Hz,C5-H), 5.52(1H,d,J=6Hz), 5.65(1H,d,J=7 Hz,C2-H), 6.29(1H,t,J=8 Hz,C13-H), 6.37(1H,s,C10-H),7.37-7.41(3H,m,ArH), 7.49-7.57(4H,m,ArH), 7.63-7.67(1H,m,ArH),8.03-8.05(2H,m,ArH).

Example 6

13-O-[3-(tert-Butoxycarbonylamino)-2-hydroxy-3-phenylpropionyl]-10-O-(4-dipropylaminopiperidinocarbonyl)-10-deacetylbaccatinIII (Compound 6)

The compound (22 mg, 0.019 mmol) of Example 5 was dissolved in methanol(4 ml), followed by the addition of methanesulfonic acid (20 mg, 0.20mmol). The resulting mixture was stirred overnight at room temperatureunder an argon gas atmosphere. A saturated aqueous solution of sodiumhydrogencarbonate was added to the reaction mixture, followed byextraction with ethyl acetate. The organic layer was washed with asaturated aqueous solution of sodium chloride, dried over anhydroussodium sulfate, and then concentrated to dryness under reduced pressure,whereby a colorless oil was obtained.

The oil was then dissolved in tetrahydrofuran (20 ml), followed by theaddition of di-tert-butyl dicarbonate (5.3 mg, 0.024 mmol) and sodiumhydrogen-carbonate (2 mg). The thus-obtained mixture was stirred at roomtemperature for 60 hours under an argon gas atmosphere. Water was addedto the reaction mixture, and the resulting mixture was extracted withethyl acetate. The organic layer was washed with a saturated aqueoussolution of sodium chloride, dried over anhydrous sodium carbonate, andthen concentrated to dryness under reduced pressure. The residue waspurified by chromatography on a silica gel column (chloroform-methanolmixed solvent [94:6)). Eluted TLC single-spot fractions were combinedtogether and then concentrated to dryness under reduced pressure,whereby a colorless oil (11 mg) was obtained. The oil was purifiedfurther by reverse-phase high-performance liquid column chromatography(eluent: 10 mM potassium dihydrogenphosphate-acetonitrile mixed solvent[1:1]).

Eluted HPLC single-peak fractions were combined together and thenconcentrated under reduced pressure. The concentrate was extracted withchloroform. The organic layer was washed with a saturated aqueoussolution of sodium chloride, dried over anhydrous sodium sulfate, andthen concentrated to dryness under reduced pressure, whereby the titlecompound (3 mg, 16%) was obtained as colorless crystals.

¹ H-NMR (CDCl₃)δ: 0.97(6H,m), 1.14(3H,s), 1.27(3H,s), 1.33(9H,s,t-Bu),1.41-2.18(8H,m), 1.66(3H,s), 1.86(3H,s), 1.86-1.92(1H,m),2.29(2H,m,C14-H), 2.38(3H,s,C4-OAc), 2.53(1H,m,C6-H), 2.55-3.60(7H,m),3.79(1H,d,J=7 Hz,C3-H), 4.17(1H,d,J=9 Hz,C20-H), 4.21-4.31(2H,m),4.30(1H,d,J=9 Hz,C20-H), 4.44(1H,s,C7-H), 4.63(1H,s,C2'-H),4.96(1H,d,J=9 Hz,C5-H), 5.27(1H,m), 5.38(1H,d,J=10 Hz,C3'-H),5.66(1H,d,J=7 Hz,C2-H), 6.25(1H,s,C13-H), 6.26(1H,s,C10-H),7.31-7.42(5H,m,ArH), 7.48-7.52(2H,m,ArH), 7.60-7.63(1H,m,ArH),8.10-8.12(2H,m,ArH). SI-MS m/z: 1018 [M+H]⁺

Example 7

10-O-(4-Piperidinopiperidinocarbonyl)-7-O-triethylsilyl-10-deacetylbaccatinIII (Compound 7)

Using 7-O-triethylsilyl-10-deacetylbaccatin III (100 mg, 0.15 mmol) and4-piperidinopiperidinocarbonyl chloride (45 mg, 0.19 mmol), reactionsand post-treatment were conducted as in Example 4, whereby the titlecompound (90 mg, 70%) was obtained as colorless crystals.

¹ H-NMR (CDCl₃)δ: 0.56-0.62(6H,m,Si--CH₂ X3), 0.92(9H,t,J=8 Hz,-MeX3),1.03(3H,s,C16 or C17-Me), 1.17(3H,s,C16 or C17-Me), 1.44(3H,m),1.60(3H,m), 1.68(3H,s,C19-Me), 1.80-1.89(4H,m), 2.19-2.34(2H,m,C14-H),2.23(3H,s,C18-Me), 2.27(3H,s,C4-OAc), 2.52(6H,m), 2.79(3H,m),3.89(1H,d,J=7 Hz,C3-H), 4.10-4.50(2H,br-s), 4.14(1H,d,J=8 Hz,C20-H),4.29(1H,d,J=8 Hz,C20-H), 4.49(1H,dd,J=7,11 Hz,C7-H), 4.80(1H,m,C13-H),4.96(1H,d,J=8 Hz,C5-H), 5.62(1H,d,J=7 Hz,C2-H), 6.38(1H,s,C10-H),7.45-7.49(2H,m,ArH), 7.57-7.61(1H,m,ArH), 8.10(2H,d,J=7 Hz,ArH). SI-MSm/z: 853 [M+H]⁺

Example 8

13-O-(4-Phenyl-2-trichloromethyl-5-oxazolidinecarbonyl)-10-O-(4-piperidinopiperidinocarbonyl)-7-O-triethylsilyl-10-deacetylbaccatinIII (Compound 8)

Using the compound (21 mg, 0.025 mmol) of Example 7, reactions andpost-treatment were conducted as in Example 5, whereby the titlecompound (22 mg, 78%) was obtained as colorless crystals.

¹ H-NMR (CDCl₃)δ: 0.57-0.61(6H,m,Si--CH₂ X3), 0.92(9H,t,J=8 Hz,-MeX3),1.21(6H,s,C16-Me and C17-Me), 1.42-1.51(3H,m), 1.62-1.71(3H,m),1.65(3H,s,C19-Me), 1.78(3H,s,C18-Me), 1.77-1.90(4H,m),2.10(3H,s,C4-OAc), 2.11-2.16(2H,m,C14-H), 2.48(1H,m,C6-H),2.48-2.98(8H,m), 3.28(1H,t,J=6 Hz,-NH--), 3.77(1H,d,J=7 Hz,C3-H),4.09(1H,d,J=8 Hz,C20-H), 4.23(1H,d,J=8 Hz,C20-H), 4.25(2H,br-s),4.44(1H,dd,J=7 Hz,11 Hz,C7-H), 4.65-4.69(1H,m), 4.74-4.78(1H,m),4.86(1H,d,J=8 Hz,C5-H), 5.52(1H,d,J=6 Hz), 5.65(1H,d,J=7 Hz,C2-H),6.28(1H,t,J=8 Hz,C13-H), 6.37(1H,s,C10-H), 7.38-7.42(3H,m,ArH),7.49-7.57(4H,m,ArH), 7.63-7.67(1H,m,ArH), 8.04(2H,d,J=7 Hz,ArH).

Example 9

13-O-[3-(tert-Butoxycarbonylamino)-2-hydroxy-3-phenylpropionyl]-10-O-(4-piperidinopiperidinocarbonyl)-10-deacetylbaccatinIII (Compound 9) Using the compound (22 mg, 0.019 mmol) of Example 8,reactions and post-treatment were conducted as in Example 6, whereby thetitle compound (3 mg, 17%) was obtained as a colorless oil.

¹ H-NMR (CDCl₃)δ: 1.14 (3H,s, C16 or C17-Me), 1.27(3H,s,C16 or C17-Me),1.33(9H,s,t-Bu), 1.41-2.20(9H,m), 1.67(3H,s,C19-Me), 1.81(4H,m,C18-Meand C6-H), 2.25-2.42(2H,m,C14-H), 2.37(3H,s,C4-OAc), 2.40-3.10(8H,m),2.50-2.57(1H,m,C6-H), 3.16(1H,s), 3.79(1H,d,J=7 Hz,C3-H), 4.17(1H,d,J=8Hz,C20-H), 4.17-4.28(2H,m), 4.30(1H,d,J=8 Hz,C20-H), 4.44(1H,dd,J=7,11Hz,C7-H), 4.63(1H,d,J=3 Hz,C2'-H), 4.96(1H,d,J=8 Hz,C5-H), 5.28(1H,m),5.36(1H,d,J=10 Hz,C3'-H), 5.66(1H,d,J=7 Hz,C2-H), 6.25(2H,m,C10-H andC13-H), 7.29-7.44(5H,mu,ArH), 7.47-7.55(2H,m,ArH), 7.59-7.64(1H,m,ArH),8.08-8.13(2H,m,ArH). SI-MS m/z: 1002 [M+H]⁺

Example 10

10-O-(4-Pyrrolidinopiperidinocarbonyl)-7-O-triethylsilyl-10-deacetylbaccatinIII (Compound 10)

1) Triphosgene (742 mg, 2.5 mmol) was dissolved in benzene (60 ml),followed by the addition of a solution of 4-pyrrolidinopiperidine (1.00g, 6.5 mmol) in benzene and triethylamine (7.5 mmol). The resultingmixture was stirred at room temperature for 17 hours. Chloroform wasadded to the reaction mixture, and the thus-obtained mixture was washedwith water. The organic layer was dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure. Theresidue was purified by chromatography on a silica gel column(chloroform-acetone mixed solvent [1:2]), whereby4-pyrrolidinopiperidinocarbonyl chloride (158 mg, 11%) was obtained.

¹ H-NMR (CDCl₃)δ: 1.50-2.15(10H,m), 2.30-2.90(5H,m), 3.02(1H,t,J=11 Hz),3.18(1H,t,J=12 Hz), 4.25(2H,d,J=12 Hz).

2) Using 4-pyrrolidinopiperidinocarbonyl chloride (95 mg, 0.44 mmol),reactions and post-treatment were conducted as in Example 1, whereby thetitle compound (169 mg, 100%) was obtained.

¹ H-NMR (CDCl₃)δ: 0.57(6H,m), 0.90(9H,t,J=8 Hz), 1.04(3H,s), 1.13(3H,s),1.65(3H,s), 2.20(3H,s), 2.27(3H,s), 1.50-2.37(13H,m), 2.51(1H,m),2.70-3.12(4H,m), 3.87(1H,d,J=7 Hz,C3-H), 4.13(1H,d,J=8 Hz,C20-H),4.29(1H,d,J=8 Hz,C20-H), 4.40(2H,br), 4.47(1H,dd,J=10,7 Hz,C7-H),4.85(1H,br,C13-H), 4.94(1H,d,J=8 Hz,C5-H), 5.61(1H,d,J=7 Hz,C2-H),6.38(1H,s,C10-H), 7.46(2H,t,J=8 Hz), 7.59(1H,t,J=7 Hz), 8.09(2H,d,J=7Hz).

Example 11

13-O-(3-Benzyloxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarbonyl)-10-O-(4-pyrrolidinopiperidinocarbonyl)-7-O-triethylsilyl-10-deacetylbaccatinIII (Compound 11)

Using the compound (169 mg, 0.20 mmol) of Example 10, reactions andpost-treatment were conducted as in Example 2, whereby the titlecompound (170 mg, 95%) was obtained.

¹ H-NMR (CDCl₃)δ: 0.56(6H,m), 0.89(9H,t,J=8 Hz), 1.15(3H,s), 1.17(3H,s),1.63(3H,s), 1.75(3H,s), 1.80(3H,s), 1.89(3H,s), 2.05(3H,s),1.45-2.28(11H,m), 2.47(1H,m), 2.70-3.23(4H,m), 3.77(1H,d,J=7 Hz,C3-H),3.50-3.75(2H,m), 4.08(1H,d,J=9 Hz,C20-H), 4.23(1H,d,J=9 Hz,C20-H),4.40(2H,br), 4.43(1H,dd,J=10 Hz,7 Hz,C7-H), 4.49(1H,d,J=6 Hz),4.85(1H,d,J=9 Hz,C5-H), 4.78-5.36(3H,m), 5.62(1H,d,J=7 Hz,C2-H),6.20(1H,br,C13-H), 6.35(1H,s,C10-H), 6.74(1H,br), 7.05-7.40(9H,m),7.47(2H,t,J=8 Hz), 7.61(1H,t,J=7 Hz), 8.02(2H,d,J=7 Hz).

Example 12

13-O-[3-(tert-Butoxycarbonylamino)-2-hydroxy-3-phenylpropionyl]-10-O-(4-pyrrolidinopiperidinocarbonyl)-10-deacetylbaccatinIII (Compound 12)

The compound (85 mg, 0.07 mmol) of Example 11 was dissolved in ethanol(5 ml), followed by the addition of 0.1 N hydrochloric acid (10 ml). Theresulting mixture was stirred at room temperature for 18 hours. Thesolvent was distilled off under reduced pressure, and chloroform wasadded to the residue. The thus-obtained mixture was washed with asaturated aqueous solution of sodium hydrogencarbonate. The organiclayer was dried over anhydrous magnesium sulfate, the solvent wasdistilled off, and methanol (10 ml), water (1 ml) and 10% palladium oncharcoal (40 mg) were then added to the residue. The resulting mixturewas stirred for 2 hours at room temperature and atmospheric pressureunder a hydrogen atmosphere. The reaction mixture was filtered through aglass filter with Celite distributed thereon. After the filtrate wasconcentrated, methylene chloride (10 ml) was added to the residue sothat the residue was dissolved. To the solution,S-tert-butoxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine (18 mg, 0.075mmol) and triethylamine (7.5 mg, 0.075 mmol) were added. The resultingmixture was stirred at room temperature for 19 hours and then at 40° C.for 6 days.

Chloroform was added to the reaction mixture, and the resulting mixturewas washed with a saturated aqueous solution of sodiumhydrogencarbonate. The organic layer was dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure. Theresidue was preliminarily purified by chromatography on a silica gelcolumn (chloroform-methanol [9:1]). Further purification was conductedby reverse-phase high-performance column chromatography (eluent: 10 mMpotassium dihydrogenphosphate-acetonitrile [3:4]), whereby the titlecompound (16 mg, 23%) was obtained.

¹ H-NMR (CDCl₃)δ: 1.10(3H,s), 1.24(3H,s), 1.31(9H,s), 1.64(3H,s),1.85(3H,s), 2.36(3H,s), 1.75-2.59(12H,m), 2.72-3.20(5H,m), 3.39(1H,br),3.77(1H,d,J=6 Hz,C3-H), 3.38-3.80(2H,m), 4.14(1H,d,J=8 Hz,C20-H),4.28(1H,d,J=8 Hz,C20-H), 4.29(2H,br), 4.41(1H,br), 4.61(1H,s,C2'-H),4.94(1H,d,J=8 Hz,C5-H), 5.18-5.42(2H,m), 5.63(1H,d,J=7 Hz,C2-H),6.23(1H,br,C13-H), 6.24(1H,s,C10-H), 7.36(5H,m), 7.48(2H,t,J=7 Hz),7.59(1H,t,J=8 Hz), 8.09(2H,d,J=7 Hz). SI-MS m/z: 988 [M+H]⁺

Example 13

10-O-(4-Morpholinopiperidinocarbonyl)-7-O-triethylsilyl-10-deacetylbaccatinIII (Compound 13)

Using 7-O-triethylsilyl-10-deacetylbaccatin III (100 mg, 0.15 mmol) and4-morpholinopiperidinocarbonyl chloride (40 mg, 0.17 mmol), reactionsand post-treatment were conducted as in Example 4, whereby the titlecompound (125 mg, 96%) was obtained as colorless crystals.

¹ H-NMR (CDCl₃)δ: 0.55-0.63(6H,m,Si--CH₂ X3), 0.92(9H,t,J=8 Hz,-MeX3),1.04(3H,s,C16 or C17-Me), 1.18(3H,s,C16 or C17-Me), 1.40-1.50(1H,m),1.66(3H,s,C19-Me), 1.82-1.93(3H,m), 2.22-2.30(2H,m,C14-H),2.25(3H,s,C18-Me), 2.28(3H,s,C4-OAc), 2.30-3.10(8H,m),2.49-2.55(1H,m,C6-H), 3.74(4H,br-s), 3.90(1H,d,J=7 Hz,C3-H),4.15(1H,d,J=8 Hz,C20-H), 4.20-4.50(2H,m), 4.30(1H,d,J=8 Hz,C20-H),4.47(1H,dd,J=7,11 Hz,C7-H), 4.82(1H,t,C13-H), 4.96(1H,d,J=8 Hz,C5-H),5.63(1H,d,J=7 Hz,C2-H), 6.38(1H,s,C10-H), 7.46-7.49(2H,m,ArH),7.58-7.62(1H,m,ArH), 8.10-8.12(2H,m,ArH).

Example 14

10-O-(4-Morpholinopiperidinocarbonyl)-13-O-(3-benzyloxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarbonyl)-7-O-triethylsilyl-10-deacetylbaccatinIII (Compound 14)

The compound (210 mg, 0.24 mmol) of Example 13 was dissolved in toluene,followed by the addition of3-benzyloxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylic acid(366 mg, 1.0 mmol), DCC (234 mg, 1.1 mmol) and DMAP (20 mg). Theresulting mixture was stirred at room temperature for 2 hours.Post-treatment was conducted as in Example 2, whereby the title compound(280 mg, 91%) was obtained.

¹ H-NMR (CDCl₃)δ: 0.57-0.61(6H,m,Si--CH₂ X3), 0.92(9H,t,J=8 Hz,-MeX3),1.19(6H,s,C16 and C17-Me), 1.40-1.50(1H,m), 1.66(3H,s,C19-Me),1.67-2.00(4H,m), 1.76(3H,s), 1.82(3H,s), 1.91(3H,s), 2.11(3H,s,C4-OAc),2.15-2.17(2H,m,C14-H), 2.45-2.52(1H,m,C6-H), 2.49-3.10(7H,m),3.75(4H,br-s), 3.80(1H,d,J=7 Hz,C3-H), 4.11(1H,d,J=8 Hz,C20-H),4.12-4.55(2H,m), 4.25(1H,d,J=8 Hz,C20-H), 4.44(1H,dd,J=7,11 Hz,C7-H),4.51(1H,d,J=6 Hz), 4.88(1H,d,J=8 Hz,C5-H), 4.98(2H,br-s), 5.24(1H,br-s),5.65(1H,d,J=7 Hz,C2-H), 6.23(1H,t,J=8 Hz,C13-H), 6.38(1H,s,C10-H),6.76(1H,br-s,ArH), 7.10-7.45(9H,m,ArH), 7.46-7.50(2H,m,ArH),7.60-7.64(1H,m,ArH), 8.03-8.05(2H,m,ArH).

Example 15

13-O-[3-(tert-Butoxycarbonylamino)-2-hydroxy-3-phenylpropionyl]-10-O-(4-morpholinopiperidinocarbonyl)-10-deacetylbaccatinIII (Compound 15)

The compound (270 mg, 0.22 mmol) of Example 14 was dissolved in ethanol(70 ml), followed by the addition of 0.1 N hydrochloric acid (22 ml, 2.2mmol). The resulting mixture was stirred at room temperature for 3 days.A saturated aqueous solution of sodium hydrogencarbonate was added tothe reaction mixture, followed by extraction with ethyl acetate. Theorganic layer was washed with a saturated aqueous solution of sodiumchloride, dried over anhydrous sodium sulfate, and then concentrated todryness under reduced pressure, whereby a colorless oil (230 mg) wasobtained.

The compound (210 mg, 0.195 mmol) was then dissolved in methanol-watermixed solvent (10:1, 22 ml), followed by the addition of 10% palladiumon charcoal (80 mg). The resulting mixture was stirred for 2.5 hours atroom temperature and atmospheric pressure under a hydrogen gasatmosphere. The reaction mixture was filtered and the filtrate wasconcentrated to dryness under reduced pressure, whereby a colorless oil(160 mg) was obtained.

This compound (70 mg, 0.077 mmol) was dissolved in tetrahydrofuran (20ml), followed by the addition of di-tert-butyl dicarbonate (20.1 mg,0.092 mmol) and sodium hydrogencarbonate (50 mg). The resulting mixturewas stirred overnight at room temperature under an argon gas atmosphere.Water was added to the reaction mixture, followed by extraction withethyl acetate. The organic layer was washed with a saturated aqueoussolution of sodium chloride, dried over anhydrous sodium sulfate, andthen concentrated to dryness under reduced pressure. The residue waspurified by chromatography on a silica gel column (chloroform-methanolmixed solvent [96:4]). TLC single-spot fractions were combined togetherand then concentrated to dryness under reduced pressure, whereby acolorless oil (63 mg, 82%) was obtained.

¹ H-NMR (CDCl₃)δ: 1.14(3H,s,C16 or C17-Me), 1.27(3H,s,C16 or C17-Me),1.33(9H,s,t-Bu), 1.56-2.00(5H,m), 1.67(3H,s,C19-Me), 1.87(3H,s,C18-Me),2.23-2.35(2H,m,C14-H), 2.37(3H,s,C4-OAc), 2.40-3.15(7H,m),2.49-2.58(1H,m,C6-H), 3.17(1H,m), 3.70-3.89(4H,m), 3.79(1H,d,J=7Hz,C3-H), 4.16-4.26(2H,m), 4.17(1H,d,J=9 Hz,C20-H), 4.30(1H,d,J=9Hz,C20-H), 4.44(1H,m,C7-H), 4.62(1H,s,C2'-H), 4.96(1H,d,J=9 Hz,C5-H),5.27(1H,m,), 5.37(1H,d,J=10 Hz,C3'-H), 5.66(1H,d,J=7 Hz,C2-H),6.24(1H,m,C13-H), 6.25(1H,s,C10-H), 7.30-7.42(5H,m,ArH),7.48-7.52(2H,m,ArH), 7.59-7.63(1H,m,ArH), 8.10-8.12(2H,m,ArH). SI-MSm/z: 1004 [M+H]⁺

Example 16

13-O-(3-Benzoylamino-2-hydroxy-3-phenylpropionyl)-10-O-(4-morpholinopiperidinocarbonyl)-10-deacetylbaccatinIII (Compound 16)

Using the compound (270 mg, 0.22 mol) of Example 14, hydrolysis wasconducted with 0.1 N hydrochloric acid in a similar manner as in Example15. Catalytic reduction was then carried out with 10% palladium oncharcoal, and post-treatment was conducted, whereby a colorless oil (160mg) was obtained.

This compound (70 mg, 0.077 mmol) was dissolved in tetrahydrofuran (20ml), followed by the addition of benzoic anhydride (21 mg, 0.092 mmol)and sodium hydrogencarbonate (50 mg). The resulting mixture was stirredovernight at room temperature under an argon gas atmosphere. Water wasadded to the reaction mixture, followed by extraction with ethylacetate. The organic layer was washed with a saturated aqueous solutionof sodium chloride, dried over anhydrous sodium sulfate, and thenconcentrated to dryness under reduced pressure. The residue was purifiedby chromatography on a silica gel column (chloroform-methanol mixedsolvent (96:41). TLC single-spot fractions were combined together andconcentrated to dryness under reduced pressure, whereby a colorless oil(65 mg, 84%) was obtained.

¹ H-NMR (CDCl₃)δ: 1.13(3H,s,C16 or C17-Me), 1.24(3H,s,C16 or C17-Me),1.56-1.95(5H,m), 1.67(3H,s,C19-Me), 1.76(1H,s), 1.81(3H,s,C18-Me),2.27-2.37(2H,m,C14-H), 2.39(3H,s,C4-OAc), 2.40-3.17(7H,m),2.50-2.58(1H,m,C6-H), 3.14(1H,m), 3.57(1H,d,J=6 Hz), 3.69-3.83(4H,m),3.79(1H,d,J=7 Hz,C3-H), 4.11-4.24(2H,m), 4.20(1H,d,J=9 Hz,C20-H),4.30(1H,d,J=9 Hz,C20-H), 4.43(1H,m,C7-H), 4.79(1H,s,C'2-H),4.96(1H,d,J=9 Hz,C5-H), 5.66(1H,d,J=7 Hz,C2-H), 5.79(1H,d,J=10Hz,C3'-H), 6.24(1H,s,C10-H), 6.25(1H,m,C13-H), 6.99(1H,d,J=9 Hz,C3'-NH),7.34-7.55(10H,m,ArH), 7.58-7.63(1H,m,ArH), 7.72-7.77(2H,m,ArH),8.11-8.15(2H,m,ArH). SI-MS m/z: 1008 [M+H]⁺

Example 17

10-O-[3-(4-Piperidinopiperidinocarbonyl)propionyl]-7-O-triethylsilyl-10-deacetylbaccatinIII (Compound 17)

1) 3-(4-Piperidinopiperidinocarbonyl)propionic acid (0.26 g, 0.97 mmol)and DCC (0.25 g, 1.2 mmol) were dissolved in methylene chloride,followed by the addition of 4-nitrothiophenol (0.23 g, 1.2 mmol). Theresulting mixture was stirred for 16 hours at 4° C. and then overnightat room temperature. The reaction mixture was filtered. After thefiltrate was concentrated, the residue was purified by chromatography ona silica gel column (chloroform-acetone mixed solvent [10:1→5:1],whereby S-4-nitrophenyl 3-(4-piperidinopiperidinocarbonyl)propanethioate(196 mg, 50%) was obtained.

¹ H-NMR (CDCl₃)δ: 1.44(4H,m), 1.59(4H,m), 1.86(2H,t,J=13 Hz),2.55(6H,m), 2.73(2H,t,J=7 Hz), 3.06(3H,m), 3.89(1H,d,J=13 Hz),4.63(1H,d,J=13 Hz), 7.62(2H,d,J=9 Hz), 8.23(2H,d,J=9 Hz),

2) 7-O-Triethylsilyl-10-deacetylbaccatin III (105 mg, 0.16 mmol) wasdissolved in THF, followed by stirring for 15 minutes over an acetonebath of -40° C. A solution of n-butyllithium (0.20 mmol) in hexane wasadded, and the resulting mixture was stirred further for 30 minutes. Tothe thus-obtained solution, a solution of the above-described thioester(94 mg, 0.23 mmol) in THF was added. The temperature of the mixture wasraised from -40° C. to room temperature, at which the mixture wasstirred overnight. Chloroform was added to the reaction mixture, and thethus-obtained mixture was washed with a saturated aqueous solution ofammonium chloride and hen with a saturated aqueous solution of sodiumhydrogencarbonate. The organic layer was dried over anhydrous magnesiumsulfate, the solvent was distilled off under reduced pressure, and theresidue was then purified by chromatography on a silica gel column(chloroform-methanol mixed solvent [10:1]), whereby the title compound(98 mg, 93%) was obtained.

¹ H-NMR (CDCl₃)δ: 0.59(6H,m), 0.92(9H,t,J=8 Hz), 1.05(3H,d,J=6 Hz),1.17(3H,d,J=3 Hz), 1.67(3H,s), 1.86(1H,m), 1.35-2.04(10H,m), 2.19(3H,s),2.29(3H,s), 2.45-2.90(10H,m), 3.05(1H,brs), 3.87(1H,d,J=7 Hz,C3-H),4.01(1H,brs), 4.13(1H,d,J=9 Hz,C20-H), 4.29(1H,d,J=8 Hz,C20-H),4.45(1H,dd,J=10,6 Hz,C7-H), 4.76(1H,brs), 4.85(1H,s,C13-H),4.95(1H,d,J=9 Hz,C5-H), 5.62(1H,d,J=7 Hz,C2-H), 6.45(1H,s,C10-H),7.47(2H,t,J=8 Hz), 7.60(1H,t,J=8 Hz), 8.10(2H,d,J=8 Hz).

Example 18

13-O-(3-Benzyloxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarbonyl)-10-O-[3-(4-piperidinopiperidinocarbonyl)propionyl]-7-O-triethylsilyl-10-deacetylbaccatinIII (Compound 18)

The compound (151 mg, 0.17 mmol) of Example 17 was dissolved in toluene,followed by the addition of3-benzyloxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylic acid(123 mg, 0.35 mmol), DCC (72 mg, 0.35 mmol) and DMAP (5 mg). Theresulting mixture was stirred overnight at room temperature. Thereaction mixture was filtered. After the filtrate was concentrated,chloroform was added to the residue. The thus-obtained mixture waswashed with a saturated aqueous solution of sodium hydrogencarbonate.The organic layer was dried over anhydrous magnesium sulfate, thesolvent was distilled off under reduced pressure, and the residue waspurified by chromatography on a silica gel column (chloroform-methanolmixed solvent [19:1]), whereby the title compound (196 mg, 94%) wasobtained.

¹ H-NMR (CDCl₃)δ: 0.56(6H,m), 0.91(9H,t,J=8 Hz), 1.19(6H,s), 1.66(3H,s),1.77(3H,s), 1.82(3H,s), 1.89(3H,s), 2.04(3H,s), 1.40-2.10(11H,m),2.15(3H,d,J=8 Hz), 2.48-3.03(8H,br), 3.78(1H,d,J=7 Hz,C3-H),4.09(1H,d,J=9 Hz,C20-H), 4.01(1H,br), 4.24(1H,d,J=8 Hz,C20-H),4.44(1H,dd,J=11,7 Hz,C7-H), 4.51(1H,d,J=6 Hz), 4.88(1H,d,J=10 Hz,C5-H),4.65-4.96(3H,br), 5.23(1H,s), 5.63(1H,d,J=7 Hz,C2-H), 6.21(1H,t,J=9Hz,C13-H), 6.40(1H,s,C10-H), 6.77(1H,br), 7.22-7.40(9H,m), 7.48(2H,t,J=8Hz), 7.62(1H,t,J=7 Hz), 8.03(2H,d,J=7 Hz).

Example 19

13-O-[3-(tert-Butoxycarbonylamino)-2-hydroxy-3-phenylpropionyl]-10-O-[3-(4-piperidinopiperidinocarbonyl)propionyl]-10-deacetylbaccatinIII (Compound 19)

The compound (98 mg, 0.079 mmol) of Example 18 was dissolved in ethanol(5 ml), followed by the addition of 0.1 N hydrochloric acid (8.5 ml).The resulting mixture was stirred at room temperature for 22 hours.After the solvent was distilled off under reduced pressure, chloroformwas added to the residue, and the thus-obtained mixture was washed witha saturated aqueous solution of sodium hydrogencarbonate. The organiclayer was dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. Methanol (10 ml), water (1 ml) and10% palladium on charcoal (40 mg) were added to the residue, followed bystirring for 4 hours at room temperature and atmospheric pressure undera hydrogen. gas atmosphere. The resulting mixture was filtered through aglass filter with Celite distributed thereon. After the filtrate wasconcentrated, methylene chloride (10 ml) was added to the residue sothat the residue was dissolved.S-tert-Butoxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine (19 mg, 0.08mmol) and triethylamine (8 mg, 0.08 mmol) were added, followed bystirring at room temperature for 6 days.

Chloroform was added to the reaction mixture, and the resulting mixturewas washed with a saturated aqueous solution of sodiumhydrogencarbonate. The organic layer was dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure. Theresidue was preliminarily purified by chromatography on a silica gelcolumn (chloroform-methanol mixed solvent [9:1]). Further purificationwas conducted by reverse-phase high-performance column chromatography(eluent: 10 mM potassium dihydrogen-phosphate-acetonitrile [3:4]),whereby the title compound (7 mg, 8%) was obtained.

¹ H-NMR (CDCl₃)δ: 1.15(3H,s), 1.26(3H,s), 1.34(9H,s), 1.67(3H,d,J=8 Hz),1.86(3H,s), 1.35-2.05(11H,m), 2.37(3H,s), 2.25-3.10(10H,m), 3.35(1H,s),3.80(1H,d,J=7 Hz,C3-H), 4.15(1H,br), 4.16(1H,d,J=9 Hz,C20-H),4.30(1H,d,J=8 Hz,C20-H), 4.39(1H,m,C7-H), 4.63(1H,s,C2'-H), 4.82(1H,br),4.94(1H,d,J=8 Hz,C5-H), 5.26(1H,s), 5.36(1H,d,J=10 Hz,C3'-H),5.66(1H,d,J=7 Hz,C2-H), 6.22(1H,br,C13-H), 6.30(1H,s,C10-H), 7.36(5H,m),7.50(2H,t,J=8 Hz), 7.61(1H,t,J=7 Hz), 8.11(2H,d,J=7 Hz). SI-MS m/z: 1058[M+H]⁺

Example 20

10-O-(4-(4-Piperidinopiperidinocarbonyl)butyryl]-7-O-triethylsilyl-10-deacetylbaccatinIII (Compound 20)

1) From 4-(4-piperidinopiperidinocarbonyl)butyric acid (0.49 g, 1.7mmol), DCC (433 mg, 2.1 mmol) and 4-nitrothiophenol (407 mg, 2.1 mmol),S-4-nitrophenyl 4-(4-piperidinopiperidinocarbonyl)butanethioate (355 mg,50%) was obtained by conducting a reaction and post-treatment as inExample 17, 1).

¹ H-NMR (CDCl₃)δ: 1.35-2.04(10H,m), 2.04(2H,m), 2.40(2H,t,J=7 Hz),2.51(6H,m), 2.82(2H,t,J=7 Hz), 2.98(1H,t,J=12 Hz), 3.87(1H,d,J=13 Hz),4.66(1H,d,J=10 Hz), 7.58(2H,d,J=9 Hz), 8.23(2H,d,J=9 Hz).

2) From 7-O-triethylsilyl-10-deacetylbaccatin III (131 mg, 0.20 mmol), asolution of n-butyllithium (0.24 mmol) and the above-described thioester(114 mg, 0.31 mmol), the title compound (169 mg, 100%) was obtained byconducting reactions and post-treatment as in Example 17, 2).

¹ H-NMR (CDCl₃)δ: 0.56(6H,m), 0.90(9H,t,J=8 Hz), 1.03(3H,d,J=3 Hz),1.15(3H,s), 1.65(3H,s), 2.16(3H,s), 2.27(3H,s), 2.20-2.90(12H,m),2.97(1H,m), 3.85(1H,d,J=7 Hz,C3-H), 4.02(1H,m), 4.12(1H,d,J=8 Hz,C20-H),4.28(1H,d,J=9 Hz,C20-H), 4.48(1H,dd,J=10,7 Hz,C7-H), 4.72(1H,br),4.83(1H,br,C13-H), 4.94(1H,d,J=9 Hz,C5-H), 5.60(1H,d,J=7 Hz,C2-H),6.48(1H,s,C10-H), 7.45(2H,t,J=8 Hz), 7.58(1H,t,J=7 Hz), 8.08(2H,d,J=8Hz).

Example 21

13-O-(3-Benzyloxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarbonyl)-10-O-[4-(4-piperidinopiperidinocarbonyl)butyryl]-7-O-triethylsilyl-10-deacetylbaccatinIII (Compound 21)

The compound (169 mg, 0.18 mmol) of Example 20 was dissolved in toluene,followed by the addition of3-benzyloxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylic acid(151 mg, 0.42 mmol), DCC (87 mg, 0.42 mmol) and DMAP (5 mg). Theresulting mixture was stirred overnight at room temperature.Post-treatment was conducted as in Example 18, whereby the titlecompound (218 mg, 96%) was obtained.

¹ H-NMR (CDCl₃)δ: 0.55(6H,m), 0.89(9H,t,J=8 Hz), 1.17(6H,s), 1.62(3H,s),1.75(3H,s), 1.81(3H,s), 1.86(3H,s), 1.86(3H,s), 2.00(3H,s),1.25-2.10(16H,m), 2.14(3H,d,J=9 Hz), 2.18-2.83(11H,m), 3.02-3.58(4H,m),3.78(1H,d,J=7 Hz,C3-H), 4.09(1H,d,J=8 Hz,C20-H), 4.13(1H,br),4.23(1H,d,J=8 Hz,C20-H), 4.44(1H,m,C7-H), 4.49(1H,d,J=6 Hz),4.85(1H,d,J=9 Hz,C5-H), 4.78-5.05(3H,m), 5.19(1H,s), 5.61(1H,d,J=7Hz,C2-H), 6.19(1H,br,C13-H), 6.45(1H,s,C10-H), 6.72(1H,br),7.09-7.45(9H,m), 7.47(2H,t,J=8 Hz), 7.61(1H,t,J=7 Hz), 8.03(2H,d,J=7Hz).

Example 22

13-O-[3-(tert-Butoxycarbonylamino)-2-hydroxy-3-phenylpropionyl]-10-O-[4-(4-piperidinopiperidinocarbonyl)butyryl]-10-deacetylbaccatinIII (Compound 22)

The compound (70 mg, 0.056 mmol) of Example 21 was dissolved in ethanol(5 ml), followed by the addition of 0.1 N hydrochloric acid (7 ml). Theresulting mixture was stirred at room temperature for 18 hours. Thesolvent was distilled off under reduced pressure, chloroform was addedto the residue, and the thus-obtained mixture was washed with asaturated aqueous solution of sodium hydrogencarbonate. The organiclayer was dried over anhydrous magnesium sulfate, the solvent wasdistilled off under reduced pressure, and methanol (10 ml), water (1 ml)and 10% palladium on charcoal (40 mg) were then added to the residue.The resulting mixture was stirred for 2 hours at room temperature andatmospheric pressure under a hydrogen gas atmosphere. The resultingmixture was filtered through a glass filter with Celite distributedthereon. After the filtrate was concentrated, methylene chloride (10 ml)was added to the residue so that the residue was dissolved.S-tert-Butoxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine (17 mg, 0.07mmol) and triethylamine (7 mg, 0.07 mmol) were added, followed bystirring at room temperature for 12 hours and further at 40° C. for 5days. Post-treatment was conducted as in Example 19, whereby the titlecompound (16 mg, 27%) was obtained.

¹ H-NMR (CDCl₃)δ: 1.12(3H,s), 1.23(3H,s), 1.32(9H,s), 1.66(3H,d,J=8 Hz),1.85(3H,s), 1.38-2.15(13H,m), 2.34(3H,s), 2.18-2.85(9H,m), 2.98(1H,m),3.79(1H,d,J=7 Hz,C3-H), 4.01(1H,br), 4.14(1H,d,J=8 Hz,C20-H),4.28(1H,d,J=8 Hz,C20-H), 4.37(1H,m,C7-H), 4.61(1H,s,C2'-H), 4.73(1H,br),4.93(1H,d,J=9 Hz,C5-H), 5.25(1H,br), 5.36(1H,d,J=9 Hz,C3'-H),5.64(1H,d,J=7 Hz,C2-H), 6.20(1H,br,C13-H), 6.32(1H,s,C10-H), 7.36(5H,m),7.49(2H,t,J=8 Hz), 7.59(1H,t,J=7 Hz), 8.08(2H,d,J=8 Hz).

SI-MS m/z: 1072 [M+H]⁺

Example 23

10-O-[(4-Piperidinopiperidinocarbonyloxy)acetyl]-7-O-triethylsilyl-10-deacetylbaccatinIII (Compound 23)

1) From (4-piperidinopiperidinocarbonyloxy)acetic acid (0.14 g, 0.50mmol), DCC (0.12 g, 0.60 mmol) and 2-fluorophenol (0.05 g, 0.60 mmol),2-fluorophenyl (4-piperidinopiperidinocarbonyloxy)acetate (97 mg, 53%)was obtained by conducting a reaction and post-treatment as in Example17, 1).

¹ H-NMR (CDCl₃)δ: 1.08-1.98(10H,m), 2.49(5H,br), 2.76(2H,br),4.22(2H,m), 4.88(2H,s), 7.16(4H,m).

2) From 7-O-triethylsilyl-10-deacetylbaccatin III (100 mg, 0.15 mmol), asolution of n-butyllithium (0.16 mmol) in hexane and the above-describedester (97 mg, 0.27 mmol), the title compound (35 mg, 76%) was obtainedby conducting reactions and post-treatment as in Example 17, 2).

¹ H-NMR (CDCl₃)δ: 0.55(6H,m), 0.90(9H,t,J=8 Hz), 1.02(3H,s), 1.14(3H,s),1.65(3H,s), 1.18-2.10(13H,m), 2.18(3H,s), 2.26(3H,s), 2.40-2.95(8H,m),3.84(1H,d,J=7 Hz,C3-H), 4.12(1H,d,J=9 Hz,C20-H), 4.27(2H,br),4.28(1H,d,J=9 Hz,C20-H), 4.46(1H,dd,J=11,7 Hz,C7-H), 4.40-4.90(3H,m),4.94(1H,d,J=8 Hz,C5-H), 5.60(1H,d,J=7 Hz,C2-H), 6.44(1H,s,C10-H),7.46(2H,t,J=8 Hz), 7.59(1H,t,J=7 Hz), 8.08(2H,d,J=7 Hz).

Example 24

13-O-(3-Benzyloxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarbonyl)-10-O-[(4-piperidinopiperidinocarbonyloxy)acetyl]-7-O-triethylsilyl-10-deacetylbaccatinIII (Compound 24)

The compound (35 mg, 0.04 mmol) of Example 23 was dissolved in toluene,followed by the addition of3-benzyloxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylic acid(34 mg, 0.10 mmol), DCC (21 mg, 0.10 mmol) and DMAP (2 mg). Theresulting mixture was stirred overnight at room temperature.Post-treatment was conducted as in Example 18, whereby the titlecompound (37 mg, 78%) was obtained.

¹ H-NMR (CDCl₃)δ: 0.56(6H,m), 0.91(9H,t,J=8 Hz), 1.19(6H,s), 1.70(3H,s),1.77(3H,s), 1.82(3H,s), 1.91(3H,s), 2.07(3H,s), 1.40-2.22(13H,m),2.47(1H,m), 2.55-3.50(7H,m), 3.76(1H,d,J=7 Hz,C3-H), 4.09(1H,d,J=8Hz,C20-H), 4.24(1H,d,J=9 Hz,C20-H), 4.34(1H,br), 4.44(1H,dd,J=10,7Hz,C7-H), 4.51(1H,d,J=6 Hz), 4.87(1H,d,J=9 Hz,C5-H), 4.50-5.15(4H,m),5.23(1H,br), 5.63(1H,d,J=7 Hz,C2-H), 6.22(1H,t,J=9 Hz,C13-H),6.42(1H,s,C10-H), 6.77(1H,br), 7.08-7.40(9H,m), 7.48(2H,t,J=8 Hz),7.62(1H,t,J=7 Hz), 8.03(2H,d,J=7 Hz).

Example 25

13-O-[3-(tert-Butoxycarbonylamino)-2-hydroxy-3-phenylpropionyl]-10-O-[(4-piperidinopiperidinocarbonyloxy)acetyl]-10-deacetylbaccatinIII (Compound 25)

Using the compound (37 mg, 0.03 mmol) of Example 24, the title compound(1 mg, 3%) was obtained by conducting reactions and treatment as inExample 19.

¹ H-NMR (CDCl₃)δ: 1.14(3H,s), 1.28(3H,s), 1.34(9H,s), 1.68(3H,s),1.87(3H,s), 1.35-1.99(13H,s), 2.38(3H,s), 2.18-2.85(8H,m), 3.37(1H,br),3.79(1H,d,J=7 Hz,C3-H), 4.16(1H,d,J=9 Hz,C20-H), 4.31(1H,d,J=8Hz,C20-H), 4.10-4.45(4H,m), 4.63(1H,s,C2'-H), 4.92(1H,br), 4.94(1H,d,J=9Hz,C5-H), 5.25(1H,br), 5.35(1H,d,J=9 Hz,C3'-H), 5.67(1H,d,J=8 Hz,C2-H),6.22(1H,br,C13-H), 6.35(1H,s,C10-H), 7.36(5H,m), 7.52(2H,t,J=8 Hz),7.60(1H,t,J=8 Hz), 8.10(2H,d,J=8 Hz). SI-MS m/z: 1060 [M+H]⁺

Example 26

10-O-[(4-Piperidinopiperidinocarbonylamino)acetyl]-7-O-triethylsilyl-10-deacetylbaccatinIII (Compound 26)

1) From (4-piperidinopiperidinocarbonylamino)acetic acid (0.14 g, 0.50mmol), DCC (0.12 g, 0.6 mmol) and 2-fluorophenol (0.05 g, 0.6 mmol),2-fluorophenyl (4-piperidinopiperidinocarbonylamino)acetate (98 mg, 54%)was obtained by conducting a reaction and post-treatment as in Example17, 1).

¹ H-NMR (CDCl₃)δ: 1.36-1.92(10H,m), 2.51(1H,br), 2.79(2H,t,J=11 Hz),4.40(2H,d,J=13 Hz), 4.31(2H,d,J=6 Hz), 5.03(1H,br), 7.16(4H,m).

2) From 7-O-triethylsilyl-10-deacetylbaccatin III (132 mg, 0.20 mmol), asolution of n-butyllithium (0.24 mmol) in hexane and the above-describedester (98 mg, 0.27 mmol), the title compound (101 mg, 79%) was obtainedby conducting reactions and post-treatment as in Example 17, 2).

¹ H-NMR (CDCl₃)δ: 0.57(6H,m), 0.92(9H,t,J=8 Hz), 1.04(3H,s), 1.16(3H,s),1.28-2.12(14H,s), 1.68(3H,s), 2.18(3H,s), 2.29(3H,s), 2.44-2.95(7H,s),3.87(1H,d,J=7 Hz,C3-H), 3.96-4.22(5H,m), 4.30(1H,d,J=8 Hz,C20-H),4.49(1H,dd,J=7,10Hz,C7-H), 4.84(1H,br,C13-H), 4.90-5.02(2H,m),5.12(1H,br), 5.62(1H,d,J=7 Hz,C2-H), 6.47(1H,s,C10-H), 7.48(2H,t,J=8Hz), 7.60(1H,t,J=7 Hz), 8.10(2H,d,J=7 Hz).

Example 27

13-O-(3-Benzyloxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarbonyl)-10-O-[(4-piperidinopiperidinocarbonylamino)acetyl]-7-O-triethylsilyl-10-deacetylbaccatinIII (Compound 27)

Using the compound (101 mg, 0.11 mmol) of Example 26, the title compound(79 mg, 58%) was obtained by conducting reactions and treatment as inExample 2.

¹ H-NMR (CDCl₃)δ: 0.54(6H,m), 0.89(9H,t,J=8 Hz), 1.16(6H,s), 1.69(3H,s),1.75(3H,s), 1.81(3H,s), 1.88(3H,s), 1.35-2.16(14H,m), 2.03(3H,s),2.42-2.88(7H,m), 3.75(1H,J=7 Hz,C3-H), 4.03-4.16(5H,m), 4.22(1H,d,J=8Hz,C20-H), 4.43(1H,dd,J=7,10Hz,C7-H), 4.49(1H,d,J=7 Hz), 4.85(1H,d,J=8Hz,C5-H), 5.04(2H,br), 5.09(1H,s), 5.21(1H,br), 5.61(1H,d,J=7 Hz,C2-H),6.19(1H,t,J=9 Hz,C13-H), 6.42(1H,s,C10-H), 6.73(1H,br), 7.10-7.40(9H,m),7.46(2H,t,J=8 Hz), 7.60(1H,t,J=7 Hz), 8.01(2H,d,J=7 Hz).

Example 28

13-O-[3-(tert-Butoxycarbonylamino)-2-hydroxy-3-phenylpropionyl]-10-O-[(4-piperidinopiperidinocarbonylamino)acetyl]-10-deacetylbaccatinIII (Compound 28)

Using the compound (79 mg, 0.06 mmol) of Example 27, the title compound(17 mg, 25%) was obtained by conducting reactions and treatment as inExample 19.

¹ H-NMR (CDCl₃)δ: 1.12(3H,s), 1.24(3H,s), 1.32(9H,s), 1.65(3H,s),1.85(3H,s), 1.50-1.98(13H,s), 2.35(3H,s), 2.25-2.87(8H,m), 3.41(1H,br),3.77(1H,d,J=7 Hz,C3-H), 4.14(1H,d,J=8 Hz,C20-H), 4.27(1H,d,J=8Hz,C20-H), 4.10-4.34(4H,m), 4.35(1H,m,C7-H), 4.61(1H,s,C2'-H),4.92(1H,d,J=9 Hz,C5-H), 5.24(1H,br), 5.41(1H,br,C3'-H), 5.60(1H,br),5.63(1H,d,J=7 Hz,C2-H), 6.20(1H,br,C13-H), 6.34(1H,s,C10-H), 7.35(5H,m),7.42(2H,t,J=8 Hz), 7.59(1H,t,J=8 Hz), 8.06(2H,d,J=8 Hz). SI-MS m/z: 1059[M+H]⁺

Example 29

10-O-[3-(4-Piperidinopiperidinocarbonylamino)propionyl]-7-O-triethylsilyl-10-deacetylbaccatinIII (Compound 29)

1) From 3-(4-piperidinopiperidinocarbonylamino)propionic acid (0.14 g,0.50 mmol), DCC (0.12 g, 0.60 mmol) and 2-fluorophenol (0.05 g, 0.6mmol), 2-fluorophenyl 3-(4-piperidinopiperidinocarbonylamino)propionate(98 mg, 52%) was obtained by conducting a reaction and post-treatment asin Example 17, 1).

¹ H-NMR (CDCl₃)δ: 1.39-1.90(10H,m), 2.29-2.65(5H,m), 2.73(2H,t,J=11 Hz),2.84(2H,t,J=6 Hz), 3.66(2H,q,J=6 Hz), 3.96(2H,d,J=13 Hz), 5.11(1H,br),7.12(4H,m).

2) From 7-O-triethylsilyl-10-deacetylbaccatin III (132 mg, 0.20 mmol), asolution of n-butyllithium (0.24 mmol) in hexane and the above-describedester (98 mg, 0.26 mmol), the title compound (92 mg, 81%) was obtainedby conducting reactions and post-treatment as in Example 17, 2).

¹ H-NMR (CDCl₃)δ: 0.58(6H,m), 0.92(9H,t,J=8 Hz), 1.05(3H,s), 1.16(3H,s),1.68(3H,s), 1.25-2.15(13H,m), 2.18(3H,s), 2.31(3H,s), 2.25-2.95(10H,m),3.61(2H,m), 3.89(1H,d,J=7 Hz,C3-H), 4.14(1H,d,J=9 Hz,C20-H),4.28(2H,br), 4.32(1H,d,J=8 Hz,C20-H), 4.52(1H,dd,J=10,7 Hz,C7-H),4.85(1H,br,C13-H), 4.97(1H,d,J=10 Hz,C5-H), 5.62(1H,d,J=7 Hz,C2-H),6.20(1H,s), 6.57(1H,s,C10-H), 7.48(2H,t,J=8 Hz), 7.61(1H,t,J=7 Hz),8.10(2H,d,J=7 Hz).

Example 30

13-O-(3-Benzyloxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarbonyl)-10-O-[3-(4-piperidinopiperidinocarbonylamino)propionyl]-7-O-triethylsilyl-10-deacetylbaccatinIII (Compound 30)

Using the compound (92 mg, 0.10 mmol) of Example 29, the title compound(107 mg, 85%) was obtained by conducting reactions and treatment as inExample 2.

¹ H-NMR (CDCl₁)δ: 0.55(6H,m), 0.89(9H,t,J=8 Hz), 1.16(3H,s), 1.18(3H,s),1.30-2.20(14H,m), 1.74(3H,s), 1.75(3H,s), 1.81(3H,s), 1.88(3H,s),2.01(3H,s), 2.42-2.83(9H,m), 3.59(2H,m), 3.78(1H,d,J=7 Hz,C3-H),4.08(1H,d,J=8 Hz,C20-H), 4.24(1H,d,J=9 Hz,C20-H), 4.30(2H,br),4.46(1H,dd,J=7,11,C7-H), 4.49(1H,d,J=7 Hz), 4.86(1H,d,J=9 Hz,C5-H),4.95(2H,br), 5.21(1H,br), 5.61(1H,d,J=7 Hz,C2-H), 6.18(1H,br),6.20(1H,br,C13-H), 6.52(1H,s,C10-H), 6.73(1H,br), 7.08-7.45(9H,m),7.47(2H,t,J=8 Hz), 7.61(1H,t,J=7 Hz), 8.01(2H,d,J=7 Hz).

Example 31

13-O-[3-(tert-Butoxycarbonylamino)-2-hydroxy-3-phenylpropionyl]-10-O-[3-(4-piperidinopiperidinocarbonylamino)propionyl]-10-deacetylbaccatinIII (Compound 31)

Using the compound (54 mg, 0.04 mmol) of Example 30, the title compound(16 mg, 35%) was obtained by conducting reactions and treatment as inExample 19.

¹ H-NMR (CDCl₃)δ: 1.14(3H,s), 1.23(3H,s), 1.32(9H,s), 1.66(3H,s),1.86(3H,s), 1.42-2.10(12H,s), 2.21-2.34(3H,m), 2.34(3H,s),2.50-2.98(7H,m), 3.52(2H,m), 3.77(1H,br), 3.80(1H,d,J=7 Hz,C3-H),4.09(1H,br), 4.13(1H,d,J=8 Hz,C20-H), 4.26(1H,br), 4.27(1H,d,J=9Hz,C20-H), 4.35(1H,m,C7-H), 4.61(1H,s,C2'-H), 4.92(1H,d,J=8 Hz,C5-H),5.23(1H,br), 5.39(1H,br,C3'-H), 5.64(1H,d,J=6 Hz,C2-H),6.18(1H,br,C13-H), 6.44(1H,s,C10-H), 7.36(5H,m), 7.48(2H,t,J=8 Hz),7.59(1H,t,J=7 Hz), 8.08(2H,d,J=8 Hz). SI-MS m/z: 1073 [M+H]⁺

Example 32

13-O-[3-Benzoylamino-2-hydroxy-3-phenylpropionyl]-10-O-[3-(4-piperidinopiperidinocarbonylamino)propionyl]-10-deacetylbaccatinIII (Compound 32)

The compound (54 mg, 0.04 mmol) of Example 30 was dissolved in ethylalcohol (4 ml), followed by the addition of 0.1 N hydrochloric acid (4ml). The resulting mixture was stirred at room temperature for 20 hours.The solvent was distilled off under reduced pressure, and the residuewas dissolved in chloroform. The thus-obtained solution was washed witha 7% aqueous solution of sodium hydrogen carbonate. The organic layerwas dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The residue was dissolved in amixed solvent consisting of methyl alcohol (5 ml) and water (0.5 ml), towhich 10% palladium on charcoal (10 mg) was added. The resulting mixturewas stirred for 2 hours at room temperature and atmospheric pressureunder a hydrogen gas atmosphere. The reaction mixture was filteredthrough a glass filter with Celite distributed thereon, and the filtratewas concentrated under reduced pressure. The residue was dissolved inmethylene chloride (5 ml), followed by the addition of benzoyl chloride(4 mg, 0.03 mmol) and triethylamine (0.03 mmol). The thus-obtainedmixture was stirred at 0° C. for 0.5 hour. Chloroform was added to thereaction mixture, and the thus-obtained mixture was washed with a 7%aqueous solution of sodium hydrogencarbonate. The organic layer wasdried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure. The residue was preliminarily purified bychromatography on a silica gel column (chloroform-methanol mixed solvent[9:1]). Further purification was conducted by reverse-phasehigh-performance column chromatography (eluent: 10 mM potassiumdihydrogen-phosphate-acetonitrile [1:1]), whereby the title compound (16mg, 35%) was obtained.

¹ H-NMR (CDCl₃)δ: 1.14(3H,s), 1.23(3H,s), 1.32(9H,s), 1.66(3H,s),1.86(3H,s), 1.42-2.10(12H,m), 2.21-2.34(3H,m), 2.34(3H,s),2.50-2.98(7H,m), 3.52(2H,m), 3.77(1H,br), 3.80(1H,d,J=7 Hz,C3-H),4.09(1H,br), 4.13(1H,d,J=8 Hz,C20-H), 4.26(1H,br), 4.27(1H,d,J=9Hz,C20-H), 4.35(1H,m,C7-H), 4.61(1H,s,C2'-H), 4.92(1H,d,J=8 Hz,C5-H),5.23(1H,br), 5.39(1H,br,C3'-H), 5.64(1H,d,J=6 Hz,C2-H),6.18(1H,br,C13-H), 6.44(1H,s,C10-H), 7.36(5H,m), 7.48(2H,t,J=8 Hz),7.59(1H,t,J=7 Hz), 8.08(2H,d,J=8 Hz). SI-MS m/z: 1077 [M+H]⁺

Example 33

10-O-(4-Benzyloxycarbonylpiperazinocarbonyl)-7-O-triethylsilyl-10-deacetylbaccatinIII (Compound 33)

Using 7-O-triethylsilyl-10-deacetylbaccatin III (100 mg, 0.15 mmol) and4-benzyloxycarbonylpiperazinocarbonyl chloride (54 mg, 0.19 mmol), thetitle compound (36 mg, 27%) was obtained as colorless crystals byconducting reactions and post-treatment as in Example 4.

¹ H-NMR (CDCl₃)δ: 0.48-0.55(6H,m,Si--CH₂ X3), 0.85(9H,t,J=8 Hz,-MeX3),0.96(3H,s,C-16 or C17-Me), 1.08(3H,s,C-16 or C17-Me), 1.60(3H,s,C19-Me),1.76-1.83(1H,m,C6-H), 2.15-2.28(2H,m,C14-H), 2.16(3H,s,C18-Me),2.21(3H,s,C4-OAc), 2.41-2.49(1H,m,C6-H), 3.26(2H,br-s), 3.40(2H,br-s),3.58(3H,br-s), 3.80(1H,br-s), 3.81(1H,d,J=7 Hz,C3-H), 4.07(1H,d,J=8Hz,C20-H), 4.23(1H,d,J=8 Hz,C20-H), 4.41(1H,dd,J=7,11 Hz,C7-H),4.75(1H,t,C13-H), 4.89(1H,d,J=8 Hz,C5-H), 5.08(2H,s,--CH₂ --)5.55(1H,d,J=7 Hz,C2-H), 6.33(1H,s,C10-H), 7.25-7.31(5H,m,ArH),7.38-7.42(2H,m,ArH), 7.51-7.54(1H,m,ArH), 8.02-8.04(2H,m,ArH). SI-MSm/z: 905 [M+H]⁺

Example 34

10-O-(4-Benzyloxycarbonylpiperazinocarbonyl)-13-O-[3-(tert-butoxycarbonyl)-2-(4-methoxyphenyl)-4-phenyl-5-oxazolidinecarbonyl]-7-O-triethylsilyl-10-deacetylbaccatinIII (Compound 34)

The compound (30 mg, 0.033 mmol) of Example 33 and3-(tert-butoxycarbonyl)-2-(4-methoxyphenyl)-4-phenyl-5-oxazolidinecarboxylicacid (53 mg, 0.13 mmol) were dissolved in toluene (10 mn), followed bythe addition of DCC (30 mg, 0.15 mmol) and DMAP (5 mg). The resultingmixture was stirred at room temperature for 5 hours under an argon gasatmosphere. A precipitate in the reaction mixture was filtered off, anda saturated aqueous solution of sodium hydrogencarbonate was added tothe filtrate. The thus-obtained mixture was extracted with ethylacetate. The organic layer was washed with a saturated aqueous solutionof sodium chloride, dried over anhydrous sodium sulfate, and thenconcentrated to dryness under reduced pressure. The residue was purifiedby chromatography on a silica gel column (chloroform). Eluted TLCsingle-spot fractions were combined together and then concentrated todryness under reduced pressure, whereby the title compound (38 mg, 90%)was obtained as a colorless oil.

¹ H-NMR (CDCl₃)δ: 0.53-0.59(6H,m,Si--CH₂ X3), 0.90(9H,t,J=8 Hz,-MeX3),1.04(9H,s,t-Bu), 1.16(6H,s,C16-Me and C17-Me), 1.63(3H,s,C19-Me),1.76(6H,s,C4-OAc and C18-Me), 1.76-1.85(1H,m,C6-H),2.10-2.16(2H,m,C14-H), 2.42-2.50(1H,m,C6-H), 3.25-3.90(8H,m),3.71(1H,d,J=7 Hz,C3-H), 3.81(3H,s,OMe), 4.08(1H,d,J=8 Hz,C20-H),4.22(1H,d,J=8 Hz,C20-H), 4.39(1H,dd,J=7 Hz,11 Hz,C7-H), 4.57(1H,d,J=6Hz,C4'-H), 4.84(1H,d,J=8 Hz,C5-H), 5.16(2H,s,--CH₂ --),5.35(1H,br-s,C2'-H), 5.61(1H,d,J=7 Hz,C2-H), 6.10(1H,t,J=8 Hz,C13-H),6.32(1H,s,C10-H), 6.34(1H,br-s,C5'-H), 6.91-6.93(2H,m,ArH),7.32-7.50(14H,m,ArH), 7.60-7.64(1H,m,ArH), 8.02-8.03(2H,m,ArH).

Example 35

10-O-(4-Benzyloxycarbonylpiperazinocarbonyl)-13-O-[3-(tert-butoxycarbonylamino)-2-hydroxy-3-phenylpropionyl]-10-O-10-deacetylbaccatinIII (Compound 35)

The compound (33 mg, 0.026 mmol) of Example 34 was dissolved in ethanol(8 ml), followed by the addition of 0.1 N hydrochloric acid (1 ml, 0.1mmol). The resulting mixture was stirred at room temperature for 3 days.A saturated aqueous solution of sodium hydrogen-carbonate was added tothe reaction mixture, followed by extraction with ethyl acetate. Theorganic layer was washed with a saturated aqueous solution of sodiumchloride, dried over anhydrous sodium sulfate, and then concentrated todryness under reduced pressure, whereby the title compound (17 mg, 63%)was obtained as a colorless oil.

¹ H-NMR (CDCl₃)δ: 1.13(3H,s,C-16 or C17-Me), 1.26(3H,s,C-16 or C17-Me),1.33(9H,s,t-Bu), 1.67(3H,s,C19-Me), 1.85-1.92(1H,m,C6-H),1.87(3H,s,C18-Me), 2.25-2.40(2H,m,C14-H), 2.37(3H,s,C4-OAc),2.50-2.58(1H,m,C6-H), 3.00(1H,s), 3.25-3.74(8H,m), 3.79(1H,d,J=7Hz,C3-H), 4.17(1H,d,J=8 Hz,C20-H), 4.30(1H,d,J=8 Hz,C20-H),4.43(1H,dd,J=7,11 Hz,C7-H), 4.62(1H,s,C2'-H), 4.96(1H,d,J=8 Hz,C5-H),5.16(2H,s,--CH₂ --), 5.28(1H,m), 5.35(1H,d,J=10 Hz,C3'-H), 5.66(1H,d,J=7Hz,C2-H), 6.25(1H,t,J=8 Hz,C13-H), 6.28(1H,s,C10-H),7.29-7.42(10H,m,ArH), 7.47-7.52(2H,m,ArH), 7.59-7.64(1H,m,ArH),8.09-8.13(2H,m,ArH).

Example 36

13-O-[3-(tert-Butoxycarbonylamino)-2-hydroxy-3-phenylpropionyl]-10-O-(piperazinocarbonyl)-10-O-deacetylbaccatinIII (Compound 36)

The compound (17 mg, 0.016 mmol) of Example 35 was dissolved in ethanol(5 ml), followed by the addition of 10% palladium on charcoal (5 mg).The resulting mixture was stirred for 7 hours at room temperature andatmospheric pressure under a hydrogen gas atmosphere. The reactionmixture was filtered, washed with chloroform and then concentrated todryness under reduced pressure, whereby a colorless oil (10 mg) wasobtained. The oil was purified by reverse-phase high-performance columnchromatography (eluent: 10 mM potassium dihydrogenphosphate-acetonitrile[1:1]). Eluted HPLC single-peak fractions were combined together,concentrated under reduced pressure, and then extracted with chloroform.The organic layer was washed with a saturated aqueous solution of sodiumchloride, dried over anhydrous sodium sulfate, and then concentrated todryness under reduced pressure, whereby the title compound (3 mg, 21%)was obtained as colorless crystals.

¹ H-NMR (CDCl₃)δ: 1.14(3H,s,C16 or C17-Me), 1.26(3H,s,C16 or C17-Me),1.33(9H,s,t-Bu), 1.67(3H,s,C19-Me), 1.85-1.92(1H,m,C6-H),1.88(3H,s,C18-Me), 2.22-2.35(2H,m,C14-H), 2.38(3H,s,C4-OAc),2.49-2.58(1H,m,C6-H), 2.80-3.05(4H,m), 3.38-3.71(4H,m), 3.80(1H,d,J=7Hz,C3-H), 4.17(1H,d,J=8 Hz,C20-H), 4.30(1H,d,J=8 Hz,C20-H),4.44(1H,dd,J=7,11 Hz,C7-H), 4.63(1H,s,C2'-H), 4.96(1H,d,J=8 Hz,C5-H),5.27(1H,m), 5.42(1H,d,J=10 Hz,C3'-H), 5.66(1H,d,J=7 Hz,C2-H),6.25(1H,t,J=8 Hz,C13-H), 6.27(1H,s,C10-H), 7.30-7.45(5H,m,ArH),7.47-7.53(2H,m,ArH), 7.59-7.64(1H,m,ArH), 8.09-8.13(2H,m,ArH). SI-MSm/z: 920 [M+H]⁺

Example 37

10-O-(4-Methylpiperazinocarbonyl)-7-O-triethylsilyl-10-deacetylbaccatinIII (Compound 37)

Using 4-methylpiperazinocarbonyl chloride (28 mg, 0.17 mmol), the titlecompound (83 mg, 70%) was obtained as colorless crystals by conductingreactions and post-treatment as in Example 4.

¹ H-NMR (CDC)δ: 0.54-0.66(6H,m,Si--CH₂ X3), 0.93(9H,t,J=8 Hz,-MeX3),1.05(3H,s,C-16 or C17-Me), 1.17(3H,s,C-16 or C17-Me), 1.68(3H,s,C19-Me),1.84-1.91(1H,m,C6-H), 2.25-2.30(2H,m,C14-H), 2.26(3H,s,C18-Me),2.29(3H,s,C4-OAc), 2.30-2.56(4H,m), 2.35(3H,s,N-Me),2.49-2.56(1H,m,C6-H), 3.41(1H,br-s), 3.54(1H,br-s), 3.70(1H,br-s),3.90(1H,br-s), 3.90(1H,d,J=7 Hz,C3-H), 4.15(1H,d,J=8 Hz,C20-H),4.30(1H,d,J=8 Hz,C20-H), 4.49(1H,dd,J=7,11 Hz,C7-H), 4.84(1H,m,C13-H),4.96(1H,d,J=8 Hz,C5-H), 5.63(1H,d,J=7 Hz,C2-H), 6.39(1H,s,C10-H),7.46-7.50(2H,m,ArH), 7.59-7.62(1H,m,ArH), 8.11(2H,d,J=7 Hz,ArH). SI-MSm/z: 785 [M+H]⁺

Example 38

10-O-(4-Methylpiperazinocarbonyl)-13-O-(4-phenyl-2-trichloromethyl-5-oxazolidinecarbonyl)-7-O-triethylsilyl-10-deacetylbaccatinIII (Compound 38)

Using the compound (20 mg, 0.025 mmol) of Example 37, the title compound(24 mg, 90%) was obtained as a colorless oil by conducting reactions andpost-treatment as in Example 5.

¹ H-NMR (CDCl₃)δ: 0.54-0.61(6H,m,Si--CH₂ X3), 0.92(9H,t,J=8 Hz,-MeX3),1.20(3H,s,C-16 or C17-Me), 1.21(3H,s,C-16 or C17-Me), 1.65(3H,s,C19-Me),1.72(1H,s), 1.78(3H,s,C18-Me), 1.77-1.84(1H,m,C6-H), 2.11(3H,s,C4-OAc),2.11-2.14(2H,m,C14-H), 2.25-2.62(4H,m), 2.36(3H,s,N-Me),2.48(1H,m,C6-H), 3.28(1H,t,J=6 Hz,-NH--), 3.42(1H,br-s), 3.53(1H,br-s),3.66(1H,br-s), 3.77(1H,d,J=7 Hz,C3-H), 3.90(1H,br-H), 4.09(1H,d,J=8Hz,C20-H), 4.23(1H,d,J=8 Hz,C20-H), 4.44(1H,dd,J=7,11 Hz,C7-H),4.67-4.69(1H,m), 4.74-4.78(1H,m), 4.86(1H,d,J=8 Hz,C5-H), 5.52(1H,d,J=6Hz), 5.65(1H,d,J=7 Hz,C2-H), 6.29(1H,t,J=8 Hz,C13-H), 6.38(1H,s,C10-H),7.39-7.42(3H,m,ArH), 7.50-7.57(4H,m,ArH), 7.63-7.67(1H,m,ArH),8.04(2H,d,J=7 Hz,ArH).

Example 39

13-O-[3-(tert-Butoxycarbonylamino)-2-hydroxy-3-phenylpropionyl]-10-O-(4-methylpiperazinocarbonyl)-10-deacetylbaccatinIII (compound 39)

Using the compound (20 mg, 0.019 mmol) of Example 38, the title compound(5 mg, 23%) was obtained as colorless crystals by conducting reactionsand post-treatment as in Example 6.

¹ H-NMR (CDCl₃)δ: 1.14(3H,s,C-16 or C17-Me), 1.27(3H,s,C-16 or C17-Me),1.33(9H,s,t-Bu), A--1.67(3H,s,C19-Me), 1.85-1.92(1H,m,C6-H),1.87(3H,s,C18-Me), 2.23-2.36(2H,m,C14-H), 2.38(3H,s,C4-OAc),2.40(3H,br-s,N--CH₃), 2.50-2.59(5H,m), 3.11(1H,br-s), 3.47-3.79(4H,m),3.80(1H,d,J=7 Hz,C3-H), 4.17(1H,d,J=9 Hz,C20-H), 4.30(1H,d,J=9Hz,C20-H), 4.44(1H,dd,J=7,11 Hz,C7-H), 4.63(1H,br-s,C2'-H),4.97(1H,d,J=8 Hz,C5-H), 5.27(1H,s), 5.36(1H,d,J=10 Hz,C3'-H),5.66(1H,d,J=7 Hz,C2-H), 6.26(1H,t,J=8 Hz,C13-H), 6.27(1H,s,C10-H),7.32-7.43(5H,m,ArH), 7.48-7.52(2H,m,ArH), 7.60-7.63(1H,m,ArH),8.11(2H,d,J=7 Hz,ArH). SI-MS m/z: 934 [M+H]⁺

Example 40

10-O-(4-Ethylpiperazinocarbonyl)-7-O-triethylsilyl-10-deacetylbaccatinIII (Compound 40)

Using 4-ethylpiperazinocarbonyl chloride (30 mg, 0.17 mmol), the titlecompound (80 mg, 66%) was obtained as colorless crystals by conductingreactions and post-treatment as in Example 4.

¹ H-NMR (CDCl₃)δ: 0.54-0.64(6H,m,Si--CH₂ x3), 0.93(9H,t,J=8 Hz,-MeX3),1.04(3H,s,C16 or C17-Me), 1.11(3H,t,J=7 Hz,ethyl-Me), 1.17(3H,s,C16 orC17-Me), 1.68(3H,s,C19-Me), 1.84-1.90(1H,m,C6-H), 2.21-2.34(4H,m),2.25(3H,s,C18-Me), 2.28(3H,s,C4-OAc), 2.45(2H,q,J=7 Hz,N--CH₂),2.50-2.60(3H,m), 3.38(1H,br-s), 3.51(1H,br-s), 3.68(1H,br-s),3.90(1H,br-s), 3.90(1H,d,J=7 Hz,C3-H), 4.15(1H,d,J=8 Hz,C20-H),4.30(1H,d,J=8 Hz,C20-H), 4.49(1H,dd,J=7,11 Hz,C7-H), 4.83(1H,m,C13-H),4.96(1H,d,J=9 Hz,C5-H), 5.63(1H,d,J=7 Hz,C2-H), 6.39(1H,s,C10-H),7.45-7.49(2H,m,ArH), 7.58-7.62(1H,m,ArH), 8.11(2H,d,J=7 Hz,ArH). SI-MSm/z: 799 [M+H]⁺

Example 41

10-O-(4-Ethylpiperazinocarbonyl)-13-O-(4-phenyl-2-trichloromethyl-5-oxazolidinecarbonyl)-7-O-triethylsilyl-10-deacetylbaccatinIII (Compound 41)

Using the compound (20 mg, 0.025 mmol) of Example 40, the title compound(25 mg, 91%) was obtained as colorless crystals by conducting reactionsand post-treatment as in Example 5.

¹ H-NMR (CDCl₃)δ: 0.54-0.61(6H,m,Si--CH₂ X3), 0.92(9H,t,J=8 Hz,-MeX3),1.11(3H,t,J=7 Hz,ethyl-Me), 1.20(3H,s,C16 or C17-Me), 1.21(3H,s,C16 orC17-Me), 1.65(3H,s,C19-Me), 1.78(3H,s,C18-Me), 1.80-1.88(1H,m,C6-H),2.12(3H,s,C4-OAc), 2.14(2H,m), 2.25-2.60(5H,m), 2.45(2H,q,J=7Hz,N--CH₂), 3.27(1H,t,J=6 Hz,-NH--), 3.40(1H,br-s), 3.50(1H,br-s),3.66(1H,br-s), 3.77(1H,d,J=7 Hz,C3-H), 3.87(1H,br-H), 4.09(1H,d,J=8Hz,C20-H), 4.23(1H,d,J=8 Hz,C20-H), 4.44(1H,dd,J=7,10 Hz,C7-H),4.67-4.69(1H,m), 4.74-4.78(1H,m), 4.87(1H,d,J=8 Hz,C5-H), 5.52(1H,d,J=6Hz), 5.65(1H,d,J=7 Hz,C2-H), 6.29(1H,t,J=11 Hz,C13-H), 6.38(1H,s,C10-H),7.35-7.45(3H,m,ArH), 7.49-7.57(4H,m,ArH), 7.63-7.65(1H,m,ArH),8.04(2H,d,J=7 Hz,ArH).

Example 42

13-O-[3-(tert-Butoxycarbonylamino)-2-hydroxy-3-phenylpropionyl]-10-O-(4-ethylpiperazinocarbonyl)-10-deacetylbaccatinIII (Compound 42)

Using the compound (20 mg, 0.019 mmol) of Example 41, the title compound(5 mg, 30%) was obtained as colorless crystals by conducting reactionsand post-treatment as in Example 6.

¹ H-NMR (CDCl₃)δ: 1.11(3H,t,J=7 Hz,ethyl-Me), 1.14(3H,s,C16 or C17-Me),1.26(3H,s,C16 or C17-Me), 1.33(9H,s,t-Bu), 1.67(3H,s,C19-Me),1.85-1.91(1H,m,C6-H), 1.87(3H,s,C18-Me), 2.22-2.35(2H,m,C14-H),2.37(3H,s,C4-OAc), 3.17(1H,br-s), 2.50-2.57(7H,m), 3.47-3.79(4H,m),3.80(1H,d,J=7 Hz,C3-H), 4.17(1H,d,J=8 Hz,C20-H), 4.30(1H,d,J=8Hz,C20-H), 4.44(1H,dd,J=7,11 Hz,C7-H), 4.63(1H,br-s,C2'-H),4.96(1H,d,J=8 Hz,C5-H), 5.27(1H,s), 5.36(1H,d,J=9 Hz,C3'-H),5.66(1H,d,J=7 Hz,C2-H), 6.25(1H,t,J=8 Hz,C13-H), 6.26(1H,s,C10-H),7.32-7.42(5H,m,ArH), 7.48-7.52(2H,m,ArH), 7.60-7.63(1H,m,ArH),8.11(2H,d,J=7 Hz,ArH). SI-MS m/z: 948[M+H]⁺

Example 43

10-O-[4-(Isopropylaminocarbonylmethyl)piperazinocarbonyl]-7-O-triethylsilyl-10-deacetylbaccatinIII (Compound 43)

Using 4-(isopropylaminocarbonylmethyl)piperazinocarbonyl chloride (42mg, 0.17 mmol), the title compound (83 mg, 70%) was obtained ascolorless crystals by conducting reactions and post-treatment as inExample 4.

¹ H-NMR (CDCl₃)δ: 0.59(6H,dq,J=3 Hz,8 Hz,Si--CH₂ X3), 0.93(9H,t,J=8Hz,-MeX3), 1.05(3H,s,C16 or C17-Me), 1.17(6H,s,C16 orC17-H,isopropyl-Me), 1.19(3H,s,isopropyl-Me), 1.68(3H,s,C19-Me),1.84-1.90(1H,m,C6-H), 2.25(3H,s,C18-Me), 2.29(3H,s,C4-OAc),2.29(2H,m,C14-H), 2.43-2.60(5H,m), 3.00(2H,d,J=3 Hz), 3.45(1H,m),3.59(2H,m), 3.87(1H,m), 3.89(1H,d,J=7 Hz,C3-H),4.08-4.15(1H,m,isopropyl-CH), 4.15(1H,d,J=8 Hz,C20-H), 4.30(1H,d,J=8Hz,C20-H), 4.49(1H,dd,J=7,11 Hz,C7-H), 4.84(1H,m,C13-H), 4.96(1H,d,J=9Hz,C5-H), 5.63(1H,d,J=7 Hz,C2-H), 6.39(1H,s,C10-H), 6.88(1H,d,J=9 Hz),7.46-7.50(2H,m,ArH), 7.59-7.62(1H,m,ArH), 8.11(2H,d,J=7 Hz,ArH). SI-MSm/z: 870 [M+H]⁺

Example 44

10-O-[4-(Isopropylaminocarbonylmethyl)piperazinocarbonyl]-13-O-(4-phenyl-2-trichloromethyl-5-oxazolidinecarbonyl)-7-O-triethylsilyl-10-deacetylbaccatinIII (Compound 44)

Using the compound (22 mg, 0.025 mmol) of Example 43, the title compound(28 mg, 97%) was obtained as colorless crystals by conducting reactionsand post-treatment as in Example 5.

¹ H-NMR (CDCl₃)δ: 0.59(6H,m,Si--CH₂ X3), 0.92(9H,t,J=8 Hz,-MeX3),1.17(3H,s), 1.19(6H,s), 1.21(3H,s), 1.65(3H,s,C19-Me),1.76(3H,s,C18-Me), 1.79-1.88(1H,m,C6-H), 2.10(3H,s,C4-OAc),2.13(2H,m,C14-H), 2.45-2.52(1H,m,C6-H), 2.56(4H,br-s), 3.01(2H,d,J=3Hz), 3.31(1H,t,J=6 Hz,-NH--), 3.45(1H,br-s), 3.59(2H,br-s),3.76(1H,d,J=7 Hz,C3-H), 3.83(1H,br-H), 4.09(1H,d,J=8 Hz,C20-H),4.07-4.13(1H,m,isopropyl-CH), 4.23(1H,d,J=8 Hz,C20-H), 4.44(1H,dd,J=7,11Hz,C7-H), 4.67-4.69(1H,m), 4.74-4.77(1H,m), 4.86(1H,d,J=8 Hz,C5-H),5.52(1H,d,J=6 Hz), 5.65(1H,d,J=7 Hz,C2-H), 6.29(1H,t,J=8 Hz,C13-H),6.38(1H,s,C10-H), 6.87-6.89(1H,d,J=8 Hz), 7.37-7.42(3H,m,ArH),7.50-7.57(4H,m,ArH), 7.64-7.67(1H,m,ArH), 8.04(2H,d,J=7 Hz,ArH).

Example 45

13-O-[3-(tert-Butoxycarbonylamino)-2-hydroxy-3-phenylpropionyl]-10-O-[4-(isopropylaminocarbonylmethyl)piperazinocarbonyl]-10-deacetylbaccatinIII (Compound 45)

Using the compound (22 mg, 0.019 mmol) of Example 44, the title compound(3 mg, 15%) was obtained as colorless crystals by conducting reactionsand post-treatment as in Example 6.

¹ H-NMR (CDCl₃)δ: 1.14(3H,s,C16 or C17-Me), 1.18(3H,s,isopropyl-Me),1.20(3H,s,isopropyl-Me), 1.26(3H,s,C16 or C17-Me), 1.33(9H,s,t-Bu),1.67(3H,s,C19-Me), 1.85-1.91(1H,m,C6-H), 1.88(3H,s,C18-Me),2.30(2H,m,C14-H), 2.38(3H,s,C4-OAc), 2.45-2.75(5H,m), 3.06(3H,s),3.47-3.70(4H,m), 3.79(1H,d,J=7 Hz,C3-H), 4.11(1H,m,isopropyl-CH),4.17(1H,d,J=8 Hz,C20-H), 4.30(1H,d,J=8 Hz,C20-H), 4.44(1H,dd,J=7,11Hz,C7-H), 4.63(1H,br-s,C2'-H), 4.96(1H,d,J=8 Hz,C5-H), 5.27(1H,m),5.37(1H,d,J=9 Hz,C3'-H), 5.66(1H,d,J=7 Hz,C2-H), 6.25(1H,t,J=8Hz,C13-H), 6.27(1H,s,C10-H), 6.88(1H,br-s), 7.26-7.41(5H,m,ArH),7.48-7.52(2H,m,ArH), 7.60-7.62(1H,m,ArH), 8.11(2H,d,J=7 Hz,ArH). SI-MSm/z: 1019 [M+H]⁺

Example 46

10-O-[3-{4-(Isopropylaminocarbonylmethyl)piperazinocarbonyl}propionyl]-7-O-triethylsilyl-10-deacetylbaccatinIII (Compound 46)

1) From 3-[4-(isopropylaminocarbonylmethyl)piperazinocarbonyl]propionicacid (0.33 g, 1.2 mmol), DCC (309 mg, 1.5 mmol) and 4-nitrothiophenol(0.23 g, 1.5 mmol), S-4-nitrophenyl3-[4-(isopropylaminocarbonylmethyl)piperazinocarbonyl]propanethioate(0.41 g, 81%) was obtained by conducting a reaction and post-treatmentas in Example 17, 1).

¹ H-NMR (CDCl₃)δ: 1.15(6H,d,J=7 Hz), 2.49(4H,m), 2.70(2H,t,J=6 Hz),2.97(2H,s), 3.06(2H,t,J=7 Hz), 3.48(2H,t,J=5 Hz), 3.62(2H,t,J=5 Hz),4.08(1H,m), 6.74(1H,s), 7.60(2H,d,J=9 Hz), 8.21(2H,d,J=9 Hz).

2) From 7-O-triethylsilyl-10-deacetylbaccatin III (66 mg, 0.16 mmol), asolution of n-butyllithium (0.14 mol) in hexane and the above-describedthioester (59 mg, 0.14 mmol), the title compound (89 mg, 97%) wasobtained by conducting reactions and post-treatment as in Example 17,2).

¹ H-NMR (CDCl₃)δ: 0.58(6H,m), 0.92(9H,t,J=8 Hz), 1.04(3H,s), 1.17(3H,s),1.18(6H,d,J=7 Hz), 1.68(3H,s), 1.87(1H,m), 2.18(3H,s), 2.29(3H,s),2.50-2.95(9H,m), 3.00(2H,s), 3.61(4H,m), 3.80(1H,d,J=7 Hz,C3-H),4.11(1H,m), 4.14(1H,d,J=9 Hz,C20-H), 4.30(1H,d,J=8 Hz,C20-H),4.48(1H,dd,J=10,7 Hz,C7-H), 4.85(1H,s,C13-H), 4.90(1H,d,J=8 Hz,C5-H),5.63(1H,d,J=7 Hz,C2-H), 6.45(1H,s,C10-H), 6.81(1H,s), 7.48(2H,t,J=8 Hz),7.60(1H,t,J=7 Hz), 8.11(2H,d,J=7 Hz).

Example 47

13-O-(3-Benzyloxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarbonyl)-10-O-[3-{4-(isopropylaminocarbonylmethyl)piperazinocarbonyl}-propionyl]-7-O-triethylsilyl-10-deacetylbaccatinIII (Compound 47)

The compound (85 mg, 0.09 mmol) of Example 46 was dissolved in toluene,followed by the addition of3-benzyloxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylic acid(164 mg, 0.47 mmol), DCC (97 mg, 0.47 mmol) and DMAP (5 mg). Theresulting mixture was stirred at room temperature for 2 days.Post-treatment was conducted as in Example 18. Purification wasconducted by chromatography on a silica gel column (chloroform-methanolmixed solvent [97:3]), whereby the title compound (113 mg, 99%) wasobtained.

¹ H-NMR (CDCl₃)δ: 0.55(6H,m), 0.91(9H,t,J=8 Hz), 1.18(6H,d,J=7 Hz),1.19(3H,s), 1.26(3H,s), 1.65(3H,s), 1.77(3H,s), 1.82(3H,s), 1.90(3H,s),2.04(3H,s), 2.18(3H,s), 1.60-2.20(4H,m), 2.69(4H,m), 2.70(2H,m),2.82(2H,m), 3.00(2H,s), 3.60(4H,m), 3.78(1H,d,J=7 Hz,C3-H), 4.09(1H,m),4.10(1H,d,J=8 Hz,C20-H), 4.24(1H,d,J=8 Hz,C20-H), 4.44(1H,dd,J=10,7Hz,C7-H), 4.51(1H,d,J=6 Hz), 4.55(1H,s), 4.87(1H,d,J=9 Hz,C5-H)4.80-5.10(2H,br), 5.55(1H,s), 5.64(1H,d,J=7 Hz,C2-H), 6.22(1H,t,J=8Hz,C13-H), 6.42(1H,s,C10-H), 6.76(1H,br), 6.85(1H,br), 7.21-7.46(9H,m),7.48(2H,t,J=7 Hz), 7.62(1H,t,J=7 Hz), 8.04(2H,d,J=7 Hz).

Example 48

13-O-[3-(tert-Butoxycarbonylamino)-2-hydroxy-3-phenylpropionyl]-10-O-[3-{4-(isopropylaminocarbonylmethyl)piperazinocarbonyl}propionyl]-10-deacetylbaccatinIII (Compound 48)

The compound (85 mg, 0.067 mmol) of Example 47 was dissolved in ethanol(8 ml), followed by the addition of 0.1 N hydrochloric acid (8 ml). Theresulting mixture was stirred at room temperature for 23 hours. Thesolvent was distilled off under reduced pressure, and chloroform wasadded to the residue. The thus-obtained mixture was washed with asaturated aqueous solution of sodium hydrogencarbonate. The organiclayer was dried over anhydrous magnesium sulfate, the solvent wasdistilled off under reduced pressure, and methanol (5 ml), water (0.5ml) and 10% palladium on charcoal (18 mg) were added to the residue. Thethus-obtained mixture was stirred for 2 hours at room temperature andatmospheric pressure under a hydrogen gas atmosphere. The resultingmixture was filtered through a glass filter with Celite distributedthereon. After the filtrate was concentrated, methylene chloride (10 ml)was added to the residue so that the residue was dissolved.S-tert-Butoxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine (19 mg, 0.08mmol) and triethylamine (8 mg, 0.08 mmol) were added, followed bystirring at room temperature for 23 hours and further at 40° C. for 6days. Post-treatment was conducted as in Example 19. Preliminarypurification was conducted by chromatography on a silica gel column(chloroform-methanol mixed solvent [97:3]). Further purification wasconducted by reverse-phase high-performance column chromatography(eluent: 10 mM potassium dihydrogen-phosphate-acetonitrile [1:1]),whereby the title compound (24 mg, 33%) was obtained.

¹ H-NMR (CDCl₃)δ: 1.12(3H,s), 1.20(6H,br), 1.24(3H,s), 1.31(9H,s),1.65(3H,s), 1.83(3H,s), 2.35(3H,s), 2.23-3.20(10H,br), 3.24-3.75(5H,br),3.79(1H,d,J=7 Hz,C3-H), 4.10(1H,m), 4.14(1H,d,J=9 Hz,C20-H),4.28(1H,d,J=9 Hz,C20-H), 4.36(1H,br,C7-H), 4.69(1H,s,C2'-H),4.93(1H,d,J=8 Hz,C5-H), 5.24(1H,br), 5.35(1H,d,J=10 Hz,C3'-H),5.65(1H,d,J=7 Hz,C2-H), 6.21(1H,br,C13-H), 6.28(1H,s,C10-H), 6.79(1H,s),7.35(5H,m), 7.48(2H,t,J=8 Hz), 7.59(1H,t,J=7 Hz), 8.09(2H,d,J=7 Hz).SI-MS m/z: 1075 [M+H]⁺

Example 49

10-O-[{4-(Isopropylaminocarbonylmethyl)piperazinocarbonyloxy}acetyl]-7-O-triethylsilyl-10-deacetylbaccatinIII (Compound 49)

1) From [4-(isopropylaminocarbonylmethyl)piperazinocarbonyloxy]aceticacid (170 mg, 0.6 mmol), DCC (0.17 g, 0.8 mmol) and 4-nitrothiophenol(0.17 g, 0.8 mmol), S-4-nitrophenyl[4-(isopropylaminocarbonylmethyl)piperazinocarbonyloxy]thioacetate (187mg, 73%) was obtained by conducting reactions and post-treatment as inExample 17, 1).

¹ H-NMR (CDCl₃)δ: 1.17(6H,d,J=7 Hz), 2.57(4H,t,J=5 Hz), 3.02(2H,s),3.63(4H,d,J=16 Hz), 4.11(1H,m), 4.96(2H,s), 6.80(1H,s), 7.61(2H,d,J=9Hz), 8.27(2H,d,J=9 Hz).

2) From 7-O-triethylsilyl-10-deacetylbaccatin III (135 mg, 0.2 mmol), asolution of n-butyllithium (0.24 mol) in hexane and the above-describedthioester (134 mg, 0.32 mmol), the title compound (0.16 g, 100%) wasobtained by conducting reactions and post-treatment as in Example 17,2).

¹ H-NMR (CDCl₃)δ: 0.59(6H,m), 0.92(9H,t,J=8 Hz), 1.04(3H,s), 1.16(3H,s),1.18(6H,d,J=7 Hz), 1.68(3H,s), 1.91(1H,m), 2.10(1H,m), 2.17(3H,s),2.28(3H,s), 2.51(5H,m), 3.00(2H,s), 3.59(4H,m), 3.86(1H,d,J=7 Hz,C3-H),4.10(1H,m), 4.14(1H,d,J=9 Hz,C20-H), 4.30(1H,d,J=8 Hz,C20-H),4.49(1H,dd,J=10,7 Hz,C7-H), 4.76(2H,m), 4.83(1H,s,C13-H), 4.95(1H,d,J=9Hz,C5-H), 5.62(1H,d,J=7 Hz,C2-H), 6.48(1H,s,C10-H), 6.83(1H,s),7.48(2H,t,J=8 Hz), 7.61(1H,t,J=7 Hz), 8.10(2H,d,J=7 Hz).

Example 50

13-O-(3-Bnzyloxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarbonyl)-10-[{4-(isopropylaminocarbonylmethyl)piperazinocarbonyloxy}acetyl]-7-O-triethylsilyl-10-deacetylbaccatinIII (Compound 50)

From the compound (155 mg, 0.17 mmol) of Example 49,3-benzyloxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazlidinecarboxylic acid(131 mg, 0.37 mmol), DCC (76 mg, 0.37 mmol) and DMAP (5 mg), the titlecompound (200 mg, 93%) was obtained by conducting reactions andpost-treatment as in Example 18.

¹ H-NMR (CDCl₃)δ: 0.56(6H,q,J=8 Hz), 0.91(9H,t,J=7 Hz), 1.19(12H,s),1.69(3H,s), 1.77(3H,s), 1.82(3H,s), 1.91(3H,s), 2.06(3H,s),1.60-2.20(4H,m), 1.55-2.10(4H,m), 2.16(2H,d,J=9 Hz), 2.52(4H,m,br),3.00(2H,s), 3.59(4H,m), 3.77(1H,d,J=7 Hz,C3-H), 4.08(1H,m),4.10(1H,d,J=9 Hz,C20-H), 4.25(1H,d,J=8 Hz,C20-H), 4.45(1H,dd,J=10,6Hz,C7-H), 4.51(1H,d,J=6 Hz), 4.87(1H,d,J=8 Hz,C5-H), 4.75-4.97(4H,m,br),5.25(1H,s), 5.64(1H,d,J=7 Hz,C2-H), 6.22(1H,t,J=9 Hz,C13-H),6.45(1H,s,C10-H), 6.77(1H,br), 6.80(1H,br), 7.23-7.47(9H,m),7.50(2H,t,J=7 Hz), 7.63(1H,t,J=7 Hz), 8.03(2H,d,J=7 Hz).

Example 51

13-O-[3-(tert-Butoxycarbonylamino)-2-hydroxy-3-phenylpropionyl]-10-O-[{4-(isopropylaminocarbonylmethyl)piperazinocarbonyloxy}acetyl]-10-deacetylbaccatinIII (Compound 51)

The compound (72 mg, 0.057 mmol) of Example 50 was dissolved in ethanol(6 ml), followed by the addition of 0.1 N hydrochloric acid (6 ml). Theresulting mixture was stirred at room temperature for 9 hours. Thesolvent was distilled off under reduced pressure, and chloroform wasadded to the residue. The thus-obtained mixture was washed with asaturated aqueous solution of sodium hydrogencarbonate. The organiclayer was dried over anhydrous magnesium sulfate, the solvent wasdistilled off under reduced pressure, and methanol (10 ml), water (1 ml)and 10% palladium on charcoal (30 mg) were then added to the residue.The thus-obtained mixture was stirred for 6 hours at room temperatureand atmospheric pressure under a hydrogen gas atmosphere. The reactionmixture was filtered through a glass filter with Celite distributedthereon. After the filtrate was concentrated, methylene chloride (10 ml)was added to the residue so that the residue was dissolved.S-tert-Butoxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine (15 mg, 0.06mmol) and triethylamine (6 mg, 0.06 mmol) were added, followed bystirring at room temperature for 2 days. Post-treatments were conductedas in Example 19, whereby the title compound (11 mg, 18%) was obtained.

¹ H-NMR (CDCl₃)δ: 1.19(3H,s), 1.22(6H,br), 1.26(3H,s), 1.34(9H,s),1.69(3H,s), 1.87(3H,s), 2.37(3H,s), 2.26-2.55(5H,m), 2.99(2H,s),3.30-3.75(5H,br), 3.79(1H,d,J=7 Hz,C3-H), 4.16(1H,d,J=9 Hz,C20-H),4.09(1H,m), 4.30(1H,d,J=8 Hz,C20-H), 4.38(1H,br,C7-H), 4.62(1H,s,C2-H),4.69-4.90(2H,br), 4.94(1H,d,J=8 Hz,C5-H), 5.26(1H,s), 5.35(1H,d,J=10Hz,C3'-H), 5.67(1H,d,J=7 Hz,C2-H), 6.22(1H,t,J=9 Hz,C13-H),6.37(1H,s,C10-H), 6.82(1H,br), 7.38(5H,m), 7.50(2H,t,J=8 Hz),7.61(1H,t,J=7 Hz), 8.11(2H,d,J=7 Hz). SI-MS m/z: 1077 [M+H]⁺

The compounds obtained above in Examples 1-51 are shown in the followingTables 1-7.

                                      TABLE 1                                     __________________________________________________________________________     ##STR10##                                                                    Comp'd No.                                                                          B--A--          E            Z                                          __________________________________________________________________________           ##STR11##      H            TES                                        2                                                                                    ##STR12##                                                                                     ##STR13##   TES                                        4                                                                                    ##STR14##      H            TES                                        5                                                                                    ##STR15##                                                                                     ##STR16##   TES                                        7                                                                                    ##STR17##      H            TES                                        8                                                                                    ##STR18##                                                                                     ##STR19##   TES                                        __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________     ##STR20##                                                                    Comp'd No.                                                                          B--A--             E            Z                                       __________________________________________________________________________    10                                                                                   ##STR21##         H            TES                                     11                                                                                   ##STR22##                                                                                        ##STR23##   TES                                     13                                                                                   ##STR24##         H            TES                                     14                                                                                   ##STR25##                                                                                        ##STR26##   TES                                     17                                                                                   ##STR27##         H            TES                                     18                                                                                   ##STR28##                                                                                        ##STR29##   TES                                     __________________________________________________________________________

                                      TABLE 3                                     __________________________________________________________________________     ##STR30##                                                                    Comp'd No.                                                                          B--A--              E            Z                                      __________________________________________________________________________    20                                                                                   ##STR31##          H            TES                                    21                                                                                   ##STR32##                                                                                         ##STR33##   TES                                    23                                                                                   ##STR34##          H            TES                                    24                                                                                   ##STR35##                                                                                         ##STR36##   TES                                    26                                                                                   ##STR37##          H            TES                                    27                                                                                   ##STR38##                                                                                         ##STR39##   TES                                    __________________________________________________________________________

                                      TABLE 4                                     __________________________________________________________________________     ##STR40##                                                                    Comp'd No.                                                                          B--A--              E            Z                                      __________________________________________________________________________    29                                                                                   ##STR41##          H            TES                                    30                                                                                   ##STR42##                                                                                         ##STR43##   TES                                    33                                                                                   ##STR44##          H            TES                                    34                                                                                   ##STR45##                                                                                         ##STR46##   TES                                    37                                                                                   ##STR47##          H            TES                                    38                                                                                   ##STR48##                                                                                         ##STR49##   TES                                    __________________________________________________________________________

                                      TABLE 5                                     __________________________________________________________________________     ##STR50##                                                                    Comp'd No.                                                                          B--A--               E            Z                                     __________________________________________________________________________    40                                                                                   ##STR51##           H            TES                                   41                                                                                   ##STR52##                                                                                          ##STR53##   TES                                   43                                                                                   ##STR54##           H            TES                                   44                                                                                   ##STR55##                                                                                          ##STR56##   TES                                   46                                                                                   ##STR57##           H            TES                                   47                                                                                   ##STR58##                                                                                          ##STR59##   TES                                   49                                                                                   ##STR60##           H            TES                                   50                                                                                   ##STR61##                                                                                          ##STR62##   TES                                   __________________________________________________________________________

                  TABLE 6                                                         ______________________________________                                         ##STR63##                                                                    Comp'd No.                                                                            B--A--                 X      Z                                       ______________________________________                                                 ##STR64##             Boc    H                                       6                                                                                      ##STR65##             Boc    H                                       9                                                                                      ##STR66##             Boc    H                                       12                                                                                     ##STR67##             Boc    H                                       15                                                                                     ##STR68##             Boc    H                                       16                                                                                     ##STR69##             Bz     H                                       19                                                                                     ##STR70##             Boc    H                                       22                                                                                     ##STR71##             Boc    H                                       25                                                                                     ##STR72##             Boc    H                                       ______________________________________                                    

                  TABLE 7                                                         ______________________________________                                         ##STR73##                                                                    Comp'd No.                                                                            B--A--                  X      Z                                      ______________________________________                                        28                                                                                     ##STR74##              Boc    H                                      31                                                                                     ##STR75##              Boc    H                                      32                                                                                     ##STR76##              Bz     H                                      35                                                                                     ##STR77##              Boc    H                                      36                                                                                     ##STR78##              Boc    H                                      39                                                                                     ##STR79##              Boc    H                                      42                                                                                     ##STR80##              Boc    H                                      45                                                                                     ##STR81##              Boc    H                                      48                                                                                     ##STR82##              Boc    H                                      50                                                                                     ##STR83##              Boc    H                                      ______________________________________                                    

Referential Example 1

13-O-(3-Benzyloxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarbonyl)-7-O-triethylsilylbaccatinIII (Compound 52)

To a mixture of 7-O-triethylsilylbaccatin III (1.39 g, 1.99 mmol),dimethylaminopyridine (DIIP, 122 mg, 1.00 mmol) andN-N-dicyclohexylcarbodiamide (DCC, 1.31 g, 6.37 mmol), a solution of3-benzyloxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylic acid(2.12 g, 5.96 mmol) in dry toluene (140 ml) was added. The resultingmixture was stirred at 80° C. for 2 hours under an argon gas atmosphere.An insoluble matter was filtered off by using a Celite pad, and thefiltrate was concentrated to dryness under reduced pressure. The residuewas purified by chromatography on a silica gel column(chloroform-n-hexane mixed solvent [1:1→2:1], whereby the title compound(1.79 g, 87%) was obtained as colorless powder. IR (KBr): 3480, 2950,1715, 1240 cm⁻¹

¹ H-NMR (CDCl₃)δ: 0.51-0.65(6H,m,Si--CH₂ X3), 0.92(9H,t,J=8 Hz,Si--CH₂CH₃ X3), 1.19(3H,s,C-16 or C-17), 1.22(3H,s,C-16 or C-17),1.66(3H,s,C-19), 1.70(1H,s,C-1:OH), 1.78(3H,br-s,oxazolidine-CH₃),1.83(3H,br-s,oxazoline-CH₃), 1.81-1.90(1H,m,C-6a),1.90(3H,s,C-10:OCOCH₃), 2.05(3H,d,J=1 Hz,C-18), 2.12-2.22(2H,m,C-14),2.18(3H,s,C-4:OCOCH₃), 2.45-2.55(1H,m,C-6b), 3.78(1H,d,J=7 Hz,C-3),4.10(1H,d,J=8 Hz,C-20a), 4.24(1H,d,J=8 Hz,C-20b), 4.45(1H,dd,J=7,11Hz,C-7), 4.51(1H,d,J=6 Hz,oxazolidine-C-4 or C-5),4.80-5.12(2H,br,Ph-CH₂ O), 4.88(1H,dd,J=2,8 Hz,C-5), 5.23(1H,br-d,J=6Hz,oxazolidine-C-4 or C-5), 5.65(1H,d,J=7 Hz,C-2), 6.22(1H,br-t.J=9Hz,C-13), 6.44(1H,s,C-10), 6.67-6.90(1H,br,Ph), 7.08-7.68(7H,m,Ph),8.04(2H,dd,J=1,8 Hz,Ph(o)).

Example 52

13-O-[3-(4-dimethylaminopiperidinocarbonylamino)-2-hydroxy-3-phenylpropionyl]-7-O-triethylsilylbaccatinIII (Compound 53)

The compound (100 mg, 0.096 mmol) of Referential Example 1 was dissolvedin a mixed solvent consisting of methanol (10 ml) and water (1 ml),followed by the addition of 10% palladium on charcoal (50 mg). Theresulting mixture was vigorously stirred at room temperature for 1.5hours under a hydrogen gas atmosphere. After full consumption of the rawmaterial was confirmed by thin layer chromatography, the catalyst wasfiltered off by using a Celite pad and the filtrate was dried withmolecular sieves 3A. The molecular sieves were filtered off and thefiltrate was concentrated to dryness under reduced pressure (40-50° C.),whereby13-O-(3-amino-2-hydroxy-3-phenylpropionyl)-7-O-triethylsilylbaccatin IIIwas obtained as colorless powder. Without purification, this crudeproduct was provided for use in the next reaction.

¹ H-NMR (CDCl₃)δ: 0.50-0.64(6H,m,Si--CH₂ X3), 0.92(9H,t,J=8 Hz,Si--CH₂CH₃ X3), 1.18(3H,s,C-16 or C-17), 1.22(3H,s,C-16 or C-17),1.67(3H,s,C-19), 1.81-1.93(1H,m,C-6a), 2.02(3H,s,C-18),2-2.18(3H,s,C-10:OCOCH₃), 2.25(3H,s,C-4:OCOCH₃), 2.45-2.58(1H,m,C-6b),3.77(1H,d,J=7 Hz,C-3), 4.13(1H,d,J=8 Hz,C-20a), 4.27(1H,d,J=8 Hz,C-20b),4.32(2H,m,C-21 and C-31), 4.44(1H,dd,J=7,11 Hz,C-7), 4.91(1H,d,J=8Hz,C-5), 5.64(1H,d,J=7 Hz,C-2), 6.12(1H,br-t,J=10 Hz,C-13),6.44(1H,s,C-10), 7.22-7.68(8H,m,C-3'-Ph and C-2-Bz(m,p)),8.06(2H,dd,J=2,9 Hz,C-2-Bz(o)).

The compound which had been obtained in the above-described reaction wasdissolved in dry pyridine (10 ml), to which4-dimethylaminopiperidinocarbonyl chloride (22 mg, 0.12 mmol) was added.The resulting mixture was stirred at room temperature for 20-24 hours.The solvent was distilled off at low temperature (ca. 30° C.) underreduced pressure, and the residue was dissolved in chloroform. Thethus-obtained mixture was washed with a 7% aqueous solution of sodiumhydrogencarbonate and then with a saturated aqueous solution of sodiumchloride. The chloroform layer was dried over sodium sulfate and thenconcentrated to dryness under reduced pressure. The residue was purifiedby chromatography on a silica gel column (chloroform-methanol mixedsolvent [9:1]), whereby the title compound (14 mg, 14%) was obtained aspale yellow powder.

¹ H-NMR (CDCl₃)δ: 0.50-0.66(6H,m,Si--CH₂ X3)1 0.93(9H,t,J=8 Hz,Si--CH₂CH₃ X3), 1.10-1.35(2H,m), 1.24(3H,s,C-16 or C-17), 1.25(3H,s,C-16 orC-17), 1.65-1.75(1H,br), 1.71(3H,s,C-19), 1.81-2.21(4H,m), 1.98(3H,d,J=1Hz,C-18), 2.10(6H,br-s,-N(CH₃)₂), 2.18(3H,s,C-10:OCOCH₃),2.27-2.58(4H,m), 2.52(3H,s,C-4:OCOCH₃), 2.85(1H,br-t,J=13 Hz),3.74(1H,br-d,J=13 Hz), 3.80(1H,d,J=7 Hz,C-3), 3.99(1H,br-d,J=13 Hz),4.26(1H,d,J=9 Hz,C-20a), 4.31(1H,d,J=9 Hz,C-20b), 4.47(1H,dd,J=7,11Hz,C-7), 4.76(1H,d,J=3 Hz,C-2'), 4.92(1H,dd,J=2,10Hz,C-5),5.49(1H,br-d,J=9 Hz,CONH), 5.56(1H,dd,J=3,9 Hz,C-31), 5.69(1H,d,J=7Hz,C-2), 6.39(1H,br-t,J=9 Hz,C-13), 6.42(1H,s,C-10),7.27-7.60(8H,m,C-3'-Ph and C-2-Bz(m,p)), 8.15(2H,dd,J=2,9 Hz,C-2-Bz(o)).

Example 53

13-O-[3-(4-Dimethylaminopiperidinocarbonylamino)-2-hydroxy-3-phenylpropionyl]baccatinIII (Compound 54)

The compound (14 mg, 0.014 mmol) of Example 52 was dissolved in ethanol(1.4 ml), followed by the addition of 0.1 N hydrochloric acid (1.4 ml)at 0° C. under stirring. The resulting mixture was stirred for 4 days.Chloroform and a 7% aqueous solution of sodium hydrogencarbonate wereadded to the reaction mixture, and the thus-obtained mixture was allowedto separate into layers. The chloroform layer was collected, washed witha saturated aqueous solution of sodium chloride, dried over anhydroussodium sulfate, and then concentrated to dryness under reduced pressure,whereby a crude product was obtained. The crude product was purified byreverse-phase high-performance liquid column chromatography (eluent: 10mM potassium dihydrogenphosphate-acetonitrile mixed solvent [7:4],detection: 225 nm), and fractions of the target compound were combinedtogether. Chloroform and a 7% aqueous solution of sodiumhydrogencarbonate were added to the thus-combined fractions, and theresulting mixture was allowed to separate into layers. The chloroformlayer was collected, washed with a saturated aqueous solution of sodiumchloride, dried over anhydrous sodium sulfate, and then concentrated todryness under reduced pressure, whereby the title compound (5 mg, 42%)was obtained as a colorless solid.

¹ H-NMR (CDCl₃)δ: 1.10-1.35(2H,m), 1.24(3H,s,C-16 or C-17),1.25(3H,s,C-16 or C-17), 1.50-1.72(1H,br), 1.69(3H,s,C-19),1.79-2.60(8H,m), 1.86(3H,d,J=1 Hz,C-18), 2.24(9H,s,-N(CH₃)₂ andC-10:OCOCH₃), 2.50(3H,s,C-4:OCOCH₃), 2.84(1H,br-t,J=13 Hz),3.78(1H,d,J=7 Hz,C-3), 3.82(1H,br-d,J=13 Hz), 4.04(1H,br-d,J=13 Hz),4.25(1H,d,J=9 Hz,C-20a), 4.31(1H,d,J=9 Hz,C-20b), 4.42(1H,dd,J=7,11Hz,C-7), 4.74(1H,d,J=3 Hz,C-21), 4.95(1H,dd,J=2,10 Hz,C-5),5.53(1H,dd,J=3,9 Hz,C-3'), 5.58-5.72(1H,br,CONH), 5.68(1H,d,J=7 Hz,C-2),6.27(1H,s,C-10), 6.39(1H,br-t,J=9 Hz,C-13), 7.27-7.62(8H,m,C-3'-Ph andC-2-Bz(m,p)), 8.15(2H,dd,J=2,9 Hz,C-2-Bz(o)). SI-MS m/z: 904 [M+H]⁺

Example 54

13-O-[3-(4-Dipropylaminopiperidinocarbonylamino)-2-hydroxy-3-phenylpropionyl]-7-O-triethylsilylbaccatinIII (Compound 55)

Using 4-dipropylaminopiperidinocarbonyl chloride (29 mg, 0.12 mmol), thetitle compound (17 mg, 17%) was obtained as a colorless solid byconducting a reaction and post-treatment as in Example 52.

¹ H-NMR (CDCl₃)δ: 0.50-0.64(6H,m,Si--CH₂ X3), 0.81(6H,t,J=7 Hz,--NCH₂CH₂ CH₃ X2), 0.92(9H,t,J=8 Hz,Si--CH₂ CH₃ X3), 1.13-1.50(7H,m),1.19(3H,s,C-16 or C-17), 1.23(3H,s,C-16 or C-17), 1.65-1.78(1H,br),1.69(3H,s,C-19), 1.83-1.97(1H,m), 1.93(3H,d,J=1 Hz,C-18),2.13-2.82(9H,m), 2.18(3H,s,C-10:OCOCH₃), 2.42(3H,s,C-4:OCOCH₃),3.79(1H,d,J=7 Hz,C-3), 3.86(1H,br-d,J=13 Hz), 3.97(1H,br-d,J=13 Hz),4.19(1H,d,J=8 Hz,C-20a), 4.29(1H,d,J=8 Hz,C-20b), 4.45(1H,dd,J=7,11Hz,C-7), 4.70(1H,d,J=3 Hz,C-2'), 4.91(1H,dd,J=2,10 Hz,C-5),5.37(1H,br-d,J=9 Hz,CONH), 5.48(1H,dd,J=3,9 Hz,C-3'), 5.68(1H,d,J=7Hz,C-2), 6.22(1H,br-t,J=9 Hz,C-13), 6.42(1H,s,C-10),7.27-7.63(8H,m,C-3'-Ph and C-2-Bz(m,p)), 8.12(2H,dd,J=2,9 Hz,C-2-Bz(o)).

Example 55

13-O-[3-(4-Dipropylaminopiperidinocarbonylamino)-2-hydroxy-3-phenylpropionyl]baccatinIII (Compound 56)

The compound (17 mg, 0.016 mmol) of Example 54 was dissolved in ethanol(1.7 ml), followed by the addition of 0.1 N hydrochloric acid (1.7 ml)at 0° C. under stirring. The resulting mixture was stirred for 3 days.The title compound (10 mg, 63%) was obtained as a colorless solid byconducting post-treatment as in Example 53.

¹ H-NMR (CDCl₃)δ: 0.90(6H,t,J=7 Hz,--NCH₂ CH₂ CH₃ X2), 1.11(2H,br-s),1.18-1.48(4H,m), 1.24(3H,s,C-16 or C-17), 1.26(3H,s,C-16 or C-17),1.50-2.15(7H,m), 1.68(3H,s,C-19), 1.83(3H,s,C-18), 2.19-2.82(6H,m),2.24(3H,s,C-10:OCOCH₃), 2.44(3H,s,C-4:OCOCH₃), 3.78(1H,d,J=7 Hz,C-3),3.97-4.33(2H,br), 4.19(1H,d,J=8 Hz,C-20a), 4.30(1H,d,J=8 Hz,C-20b),4.41(1H,dd,J=7,11 Hz.C-7), 4.68(1H,d,J=4 Hz,C-2'), 4.95(1H,dd,J=2,10Hz,C-5), 5.46(1H,dd,J=4,9 Hz,C-31), 5.66(1H,d,J=7 Hz,C-2),6.26(1H,br-t,J=9 Hz,C-13), 6.27(1H,s,C-10), 7.24-7.65(8H,m,C-31-Ph, andC-2-Bz(m,p)), 8.14(2H,dd,J=1,8 Hz,C-2-Bz(o)). SI-MS m/z: 960 [M+H]⁺

Example 56

13-O-[2-Hydroxy-3-phenyl-3-(4-piperidinopiperidinocarbonylamino)propionyl]-7-O-triethylsilylbaccatinIII (Compound 57)

Using 4-piperidinopiperidinocarbonyl chloride (PPC, 24 mg, 0.11 mmol),the title compound (35 mg, 34%) was obtained as a yellow solid byconducting a reaction and post-treatment as in Example 52.

¹ H-NMR (CDCl₃)δ: 0.51-0.65(6H,m,Si--CH₂ X3), 0.92(9H,t,J=8 Hz,Si--CH₂CH₃ X3), 1.21(3H,s,C-16 or C-17), 1.24(3H,s,C-16 or C-17),1.20-2.88(21H,m,pp,C-6a,C-6b and C-14), 1.70(3H,s,C-19),1.95(3H,s,C-18), 2.18(3H,s,C-10:OCOCH₃), 2.45(3H,s,C-4:OCOCH₃),3.79(1H,d,J=7 Hz,C-3), 3.84(1H,br-d,J=12 Hz,pp), 4.00(1H,br-d,J=12Hz,pp), 4.21(1H,d,J=8 Hz,C-20a), 4.30(1H,d,J=8 Hz,C-20b),4.46(1H,dd,J=7,11 Hz,C-7), 4.71(1H,d,J=3 Hz,C-21), 4.92(1H,dd,J=1,10Hz,C-5), 5.41(1H,br-d,J=9 Hz,CONH), 5.50(1H,dd,J=3,9 Hz,C-3'),5.68(1H,d,J=7 Hz,C-2), 6.28(1H,br-t,J=9 Hz,C-13), 6.42(1H,s,C-10),7.27-7.43(5H,m,C-3'-Ph), 7.47-7.63(3H,m,C-2-Bz(m,p)), 8.12(2H,dd,J=2,9Hz,C-2-Bz(o)).

Example 57

13-O-[2-Hydroxy-3-phenyl-3-(4-piperidinopiperidinocarbonylamino)propionyl]baccatinIII (Compound 58)

The compound (33 mg, 0.031 mmol) of Example 56 was dissolved in ethanol(4 ml), followed by the addition of 0.1 N hydrochloric acid (4 ml) at 0°C. under stirring. The resulting mixture was stirred for 4 days.Post-treatment and purification were conducted as in Example 53, wherebythe title compound (24 mg, 83%) was obtained as a pale yellow solid.

¹ H-NMR (CDCl₃)δ: 1.11(3H,s,C-16 or C-17), 1.23(3H,s,C-16 or C-17),1.20-2.83(21H,m,pp,C-6a,C-6b and C-14), 1.68(3H,s,C-19),1.83(3H,s,C-18), 2.24(3H,s,C-10:OCOCH₃), 2.45(3H,s,C-4:OCOCH₃),3.77(1H,d,J=7 Hz,C-3), 3.97(1H,br-d,J=12 Hz,pp), 4.11(1H,br-d,J=12Hz,pp), 4.20(1H,d,J=8 Hz,C-20a), 4.30(1H,d,J=8 Hz,C-20b),4.40(1H,dd,J=7,11 Hz,C-7), 4.69(1H,d,J=3 Hz,C-2'), 4.94(1H,dd,J=1,10Hz,C-5), 5.46(1H,dd,J=3,9 Hz,C-31), 5.65(1H,d,J=7 Hz,C-2),5.70-6.02(1H,br,CONH), 6.26(1H,s,C-10), 6.30(1H,br-t,J=9 Hz,C-13),7.25-7.43(5H,m,C-31-Ph), 7.48-7.64(3H,m,C-2-Bz(m,p)), 8.13(2H,dd,J=2,9Hz,C-2-Bz(o)). SI-MS m/z: 944 [M+H]⁺

Example 58

13-O-[2-Hydroxy-3-phenyl-3-(4-pyrrolidinopiperidinocarbonylamino)propionyl]-7-O-triethylsilylbaccatinIII (Compound 59)

Using 4-pyrrolidinopiperidinocarbonyl chloride (25 mg, 0.12 mmol), thetitle compound (15 mg, 15%) was obtained as a pale yellow solid byconducting a reaction and post-treatment as in Example 52.

¹ H-NMR (CDCl₃)δ: 0.50-0.65(6H,m,Si--CH₂ X3), 0.93(9H,t,J=8 Hz,Si--CH₂CH X3), 1.18(3H,s,C-16 or C-17), 1.22(3H,s,C-16 or C-17),1.26(2H,br-s,pip), 1.63-2.58(16H,m,pip,pyr,C-6a,C-6b and C-14),1.72(3H,s,C-19), 1.99(3H,d,J=1 Hz,C-18), 2.18(3H,s,C-10:OCOCH₃),2.55(3H,s,C-4:OCOCH₃), 2.88(1H,br-t,J=13 Hz), 3.58-3.73(1H,br-m),3.79(1H,d,J=7 Hz,C-3), 3.98-4.02(1H,br-m), 4.28(1H,d,J=8 Hz,C-20a),4.31(1H,d,J=8 Hz,C-20b), 4.47(1H,dd,J=7,11 Hz,C-7), 4.77(1H,d,J=2Hz,C-21), 4.93(1H,dd,J=2,10Hz,C-5), 5.43-5.56(1H,br,CONH),5.57(1H,dd,J=2,9 Hz,C-3'), 5.67(1H,d,J=7 Hz,C-2), 6.41(1H,br-t,J=9Hz,C-13), 6.41(1H,s,C-10), 7.27-7.57(8H,m,C-3'-Ph and C-2-Bz(m,p)),8.15(2H,dd,J=2,8 Hz,C-2-Bz(o)).

Example 59

13-O-[2-Hydroxy-3-phenyl-3-(4-pyrrolidinopiperidinocarbonylamino)propionyl]baccatinIII (Compound 60)

The compound (15 mg, 0.014 mmol) of Example 58 was dissolved in ethanol(1.5 ml), followed by the addition of 0.1 N hydrochloric acid (1.5 ml)at 0° C. under stirring. The resulting mixture was stirred for 4 days.Post-treatment and purification were conducted as in Example 53, wherebythe title compound (9 mg, 65%) was obtained as a colorless solid.

¹ H-NMR (CDCl₃)δ: 1.09(3H,s,C-16 or C-17), 1.22(3H,s,C-16 or C-17),1.25(2H,br-s,pip), 1.40-2.95(17H,m,pip,pyr,C-6a,C-6b and C-14),1.68(3H,s,C-19), 1.85(3H,d,J=1 Hz,C-18), 2.23(3H,s,C-10:OCOCH₃),2.48(3H,s,C-4:OCOCH₃), 3.77(1H,d,J=7 Hz,C-3), 3.90-4.20(2H,br-m),4.23(1H,d,J=8 Hz,C-20a), 4.29(1H,d,J=8 Hz,C-20b), 4.41(1H,dd,J=7,11Hz,C-7), 4.71(1H,d,J=3 Hz,C-21), 4.94(1H,dd,J=2,10 Hz,c-5),5.51(1H,dd,J=3,9 Hz,C-3'), 5.65(1H,d,J=7 Hz,C-2), 6.26(1H,s,C-10),6.34(1H,br-t,J=9 Hz,C-13), 7.24-7.62(8H,m,C-3'-Ph and C-2-Bz(m,p)),8.14(2H,dd,J=2,9 Hz,C-2-Bz(o)). SI-MS m/z: 930 [M+H]⁺

Example 60

13-O-[2-Hydroxy-3-(4-morpholinopiperidinocarbonylamino)-3-phenylpropionyl]-7-O-triethylsilylbaccatinIII (Compound 61)

Using 4-morpholinopiperidinocarbonyl chloride (27 mg, 0.12 mmol), thetitle compound (45 mg, 44%) was obtained as a yellow solid by conductinga reaction and post-treatment as in Example 52.

¹ H-NMR (CDCl₃)δ: 0.50-0.65(6H,m,Si--CH₂ X3), 0.93(9H,t,J=8 Hz,Si--CH₂CH₃ X3), 1.10-1.40(3H,br-m,pp), 1.20(3H,s,C-16 or C-17), 1.25(3H,s,C-16or C-17), 1.62-2.63(9H,m,pp,mor,C-6a,C-6b and C-14), 1.70(3H,s,C-19),1.96(3H,s,C-18), 2.18(3H,s,C-10:OCOCH₃), 2.46(3H,s,C-4:OCOCH₃),2.73-2.98(2H,m), 3.58-3.86(5H,m,mor and pp), 3.79(1H,d,J=7 Hz,C-3),3.97(1H,br-d,J=14 Hz,pp), 4.21(1H,d,J=8 Hz,C-20a), 4.30(1H,d,J=8Hz,C-20b), 4.46(1H,dd,J=7,11 Hz,C-7), 4.72(1H,d,J=3 Hz,C-21),4.91(1H,dd,J=1,9 Hz,C-5), 5.42(1H,d,J=9 Hz,CONH), 5.51(1H,dd,J=3,9Hz,C-31), 5.69(1H,d,J=7 Hz,C-2), 6.29(1H,br-t,J=9 Hz,C-13),6.42(1H,s,C-10), 7.25-7.62(8H,m,C-3'-Ph and C-2-Bz(m,p)),8.12(2H,dd,J=2,9 Hz,C-2-Bz(o)).

Example 61

13-O-[2-Hydroxy-3-(4-morpholinopiperidinocarbonylamino)-3-phenylpropionyl]baccatinIII (Compound 62)

The compound (45 mg, 0.042 mmol) of Example 60 was dissolved in ethanol(4.5 ml), followed by the addition of 0.1 N hydrochloric acid (4.5 ml)at 0° C. under stirring. The resulting mixture was stirred for 2 days.Post-treatment and purification were conducted as in Example 53, wherebythe title compound (25 mg, 63%) was obtained as a colorless solid.

¹ H-NMR (CDCl₃)δ: 1.08-1.39(4H,br-m,pp), 1.16(3H,s,C-16 or C-17),1.26(3H,s,C-16 or C-17), 1.68(3H,s,C-19), 1.80-1.93(2H,m),1.84(3H,s,C-18), 2.05-2.64(7H,m,C-6a,C-6b,C-14,pp and mor),2.24(3H,s,C-10:OCOCH₃), 2.46(3H,s,C-4:OCOCH₃), 2.78-2.98(2H,m),3.58-3.75(4H,m,mor), 3.77(1H,d,J=7 Hz,C-3), 3.80(1H,br-d,J=13 Hz,pp),3.96(1H,br-d,J=13 Hz,pp), 4.22(1H,d,J=8 Hz,C-20a), 4.30(1H,d,J=8Hz,C-20b), 4.41(1H,dd,J=7,11 Hz,C-7), 4.72(1H,d,J=3 Hz,C-2'),4.94(1H,dd,J=2,10Hz,C-5), 5.42(1H,d,J=9 Hz,CONH), 5.50(1H,dd,J=3,9Hz,C-31), 5.68(1H,d,J=7 Hz,C-2), 6.28(1H,s,C-10), 6.33(1H,br-t.J=9Hz,C-13), 7.26-7.44(5H,m,C-31-Ph), 7.47-7.63(3H,m,C-2-Bz(m,p)),8.12(2H,dd,J=2,9 Hz,C-2-Bz(o)). SI-MS mn/z: 946 [M+H]⁺

Example 62

13-O-[2-Hydroxy-3-phenyl-3-{3-(4-piperidinopiperidinocarbonyl)propionylamino}propionyl]-7-O-triethylsilylbaccatinIII (Compound 63)

3-(4-Piperidinopiperidinocarbonyl)propionic acid (29 mg, 0.12 mmol) wasdissolved in dry methylene chloride (10 ml), followed by the addition ofDCC (26 mg, 0.13 mmol). The resulting mixture was stirred at roomtemperature for 0.5 hour. To a solution of13-O-(3-amino-2-hydroxy-3-phenylpropionyl)-7-O-triethylsilylbaccatinIII, which had been prepared by conducting a reaction and post-treatmentas in Example 52, in dry methylene chloride (10 ml), the above mixturewas added and sodium hydrogencarbonate (9 mg, 0.11 mmol) was addedfurther. The resulting mixture was stirred at room temperature for 21hours. An insoluble matter was filtered off and the filtrate was thenconcentrated to dryness under reduced pressure, whereby a crude productwas obtained. The crude product was purified by medium-pressurechromatography on a silica gel column (eluent: chloroform-methanol mixedsolvent [9:1], detection: 225 nm) and reverse-phase high-performanceliquid column chromatography (eluent: 10 mM potassiumdihydrogenphosphate-acetonitrile mixed solvent [2:5], detection: 225nm). Fractions containing the target compound were combined together.Chloroform and a 7% aqueous solution of sodium hydrogencarbonate wereadded to the thus-combined fractions, and the resulting mixture wasallowed to separate into layers. The chloroform layer was washed with asaturated aqueous solution of sodium chloride, dried over anhydroussodium sulfate, and then concentrated to dryness under reduced pressure,whereby the title compound (35 mg, 32%) was obtained as a pale yellowsolid.

¹ H-NMR (CDCl₃)δ: 0.44-0.60(6H,m,Si--CH₂ X3), 0.87(9H,t,J=8 Hz,Si--CH₂CH₃ X3), 1.00-3.00(m), 3.40-4.00(6H,m), 4.01(1H,d,J=9 Hz,C-20a),4.05(1H,d,J=9 Hz,C-20b), 4.20(4H,m), 4.46-4.55(1H,m,C-7), 4.76(1H,d,J=3Hz,C-21), 4.92(1H,d,J=9 Hz,C-5), 5.27-5.39(1H,m,C-31), 5.45(1H,d,J=7Hz,C-2), 5.77-5.87(1H,m), 5.97(1H,q-like,C-13), 6.29(1H,s,C-10),7.19-7.39(5H,m), 7.55-7.72(3H,m), 8.01(1H,d,J=7 Hz), 8.26(1H,d,J=8 Hz),8.41(1H,br-d,J=6 Hz,CONH).

Example 63

13-O-C2-Hydroxy-3-phenyl-3-{3-(4-piperidinopiperidinocarbonyl)propionylamino}propionyl)baccatin III (Compound 64)

The compound (35 mg, 0.031 mmol) of Example 62 was dissolved in ethanol(3.5 ml), followed by the addition of 0.1 N hydrochloric acid (3.5 ml)at 0° C. under stirring. The resulting mixture was stirred for 4 days.Post-treatment and purification were conducted as in Example 53, wherebythe title compound (24 mg, 77%) was obtained as a colorless solid.

¹ H-NMR (DMSO-d₆, 60° C.)δ: 1.07(3H,s,C-16 or C-17), 1.09(3H,s,C-16 orC-17), 1.20-3.35(m), 1.53(3H,s,C-19), 1.84(3H,d,J=1 Hz,C-18),2.12(3H,s,C-10:OCOCH₃), 2.27(3H,s,C-4:OCOCH₃), 3.67(1H,d,J=7 Hz,C-3),4.01(1H,d,J=8 Hz,C-20a), 4.07(1H,d,J=8 Hz,C-20b), 4.14(1H,m,C-7),4.49(1H,dd,J=5,6 Hz,C-21), 4.57(1H,s,C-1:OH), 4.69(1H,d,7 Hz,C-7:OH),4.90(1H,dd,J=2,10 Hz,C-5), 5.32(1H,dd,J=5,9 Hz,C-31), 5.47(1H,d,J=7Hz,C-2), 5.71(1H,br-d,J=6 Hz,C-2:OH), 5.98(1H,br-t,J=9 Hz,C-13),6.32(1H,s,C-10), 7.18-7.40(5H,m,C-3'-Ph), 7.52-7.72(3H,m,C-2-Bz(m,p)),8.01(2H,dd,J=2,8 Hz,C-2-Bz(o)), 8.29(1H,d,J=9 Hz,CONH). SI-MS m/z: 1000[M+H]⁺

Example 64

13-O-[2-Hydroxy-3-phenyl-3-{4-(4-piperidinopiperidinocarbonyl)butyrylamino}propionyl]-10-deacetylbaccatinIII (Compound 65)

13-O-(3-Amino-2-hydroxy-3-phenylpropionyl)-7,10-bis-O-(2,2,2-trichloroethoxycarbonyl)-10-deacetylbaccatinIII (106 mg, 0.10 mmol) and 4-(4-piperidinopiperidinocarbonyl)butyricacid (34 mg, 0.12 mmol) were dissolved in toluene (10 ml), followed bythe addition of DCC (25 mg, 0.12 mmol). The resulting mixture wasstirred at room temperature for 60 hours. A precipitate in the reactionmixture was filtered off, followed by the addition of a saturatedaqueous solution of sodium hydrogencarbonate (50 ml) to the filtrate.The thus-obtained mixture was extracted with chloroform. The organiclayer was dried over anhydrous magnesium sulfate and then concentratedto dryness under reduced pressure. The residue was purified bychromatography on a silica gel column (chloroform-methanol mixed solvent[19:1]). Eluted TLC single-spot fractions were combined together andthen concentrated to dryness under reduced pressure, whereby the titlecompound (32 mg, 24%) was obtained as colorless crystals.

Subsequently, the crystals (30 mg, 0.022 mmol) was dissolved in aceticacid-methanol (1:1) mixed solvent (2 ml), followed by the addition ofzinc powder (35 mg). The resulting mixture was stirred at 90° C. for 8hours. A precipitate in the reaction mixture was filtered off, and waterwas added to the filtrate. The thus-obtained mixture was extracted withchloroform. The organic layer was washed with a saturated aqueoussolution of sodium hydrogencarbonate and a saturated aqueous solution ofsodium chloride, dried over anhydrous magnesium sulfate, and thenconcentrated to dryness under reduced pressure. The residue was purifiedby chromatography on a silica gel column (chloroform-methanol mixedsolvent [19:1]). Eluted TLC single-spot fractions were combined togetherand then concentrated to dryness under reduced pressure, whereby thetitle compound (4 mg, 18%) was obtained as colorless crystals.

¹ H-NMR (CDCl₃)δ: 1.12(3H,s), 1.25(3H,s), 1.26-1.50(2H,m),1.74(3H,s,C19-Me), 1.84(3H,s,C18-Me), 1.62-1.98(7H,m),2.51(3H,s,C4-OAc), 2.55(3H,s), 2.52-2.65(8H,m), 2.80-2.95(2H,m),3.64-3.76(3H,m), 3.91(1H,d,J=8 Hz,C3-H), 4.37(1H,d,J=9 Hz,C20-H),4.47(1H,d,J=9 Hz,C20-H), 4.66(1H,m), 4.78(1H,dd,J=8,11 Hz,C7-H),4.91(1H,m,C5-H), 5.44(1H,s,C10-H), 5.64(1H,m,C3'-H), 5.76(1H,m,C2-H),6.35(1H,m,C13-H), 7.00(1H,m), 7.24-7.58(8H,m,ArH), 8.19(2H,m,ArH). SI-MSm/z: 972 [M+H]⁺

Example 65

13-O-[2-Hydroxy-3-phenyl-3-{(4-piperidino-piperidinocarbonylamino)acetylamino}propionyl]-10-deacetylbaccatinIII (Compound 66)

13-O-(2-Amino-3-hydroxy-3-phenylpropionyl)-7,10-bis-O-(2,2,2-trichloroethoxycarbonyl)-10-deacetylbaccatinIII (107 mg, 0.10 mmol), (4-piperidinopiperidinocarbonylamino)aceticacid (30 mg, 0.11 mmol) and DCC (23 mg, 0.11 mmol) were dissolved inmethylene chloride, and the resultant solution was stirred over-night atroom temperature and further for 3 hours at 45° C.

The reaction mixture was filtered. After the filtrate was concentrated,chloroform was added to the residue. The resulting mixture was washedwith a saturated aqueous solution of sodium hydrogencarbonate. Theorganic layer was dried over anhydrous magnesium sulfate, and thesolvent was then distilled off under reduced pressure. The residue waspurified by chromatography on a silica gel column (chloroform-methanolmixed solvent [9:1→7:3)), whereby a purified product (96 mg) wasobtained. Methanol (1 ml) and acetic acid (1 ml) were added to thepurified product so that the purified product was dissolved. Zinc powder(65 mg) was added to the resultant solution, followed by stirring at 60°C. for 36 hours. Chloroform was added to the reaction mixture, and theresultant mixture was washed with a saturated aqueous solution of sodiumhydrogencarbonate. The organic layer was dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure. Theresidue was preliminarily purified by chromatography on a silica gelcolumn (chloroform-methanol mixed solvent [7:3]). Further purificationwas conducted by reverse-phase high-performance liquid columnchromatography (eluent: acetonitrile-water-trifluoro-acetic acid mixedsolvent (200:100:0.3]. Fractions containing the target compound werecombined together, followed by the addition of chloroform and a 7%aqueous solution of sodium hydrogencarbonate. The thus-obtained mixturewas allowed to separate into layers. The chloroform layer was washedwith a saturated aqueous solution of sodium chloride, dried overanhydrous sodium sulfate, and then concentrated to dryness under reducedpressure, whereby the title compound (1 mg, 1%) was obtained.

¹ H-NMR (CDCl₃)δ: 1.06(3H,s), 1.36(3H,s), 1.70(3H,s), 1.81(3H,s),2.34(3H,s), 1.00-2.58(16H,m), 2.60-3.00(4H,m), 3.44-4.21(9H,m),4.62(1H,d,J=2 Hz,C2'-H), 4.85(1H,d,J=9 Hz,C5-H), 5.12(1H,s,C10-H),5.51(1H,d,J=9 Hz,C3'-H), 5.61(1H,d,J=7 Hz,C2-H), 6.23(1H,t,J=9Hz,C13-H), 6.93(1H,s), 7.30(5H,m), 7.44(2H,t,J=8 Hz), 7.51(1H,t,J=7 Hz),8.08(2H,d,J=7 Hz). SI-MS m/z: 959 [M+H]⁺

Example 66

13-O-[2-Hydroxy-3-phenyl-3-(4-(4-piperidinopiperidinocarbonyloxy)benzoylamino)propionyl]-7,10-bis-O-(2,2,2-trichloroethoxycarbonyl)-10-deacetylbaccatinIII (Compound 67) 4-(4-Piperidinopiperidinocarbonyloxy)benzoic acid (37mg, 0.11 mmol) was dissolved in tetrahydrofuran (5 ml), followed by theaddition of triethylamine (11 mg, 0.11 mmol) and ethyl chloroformate (12mg, 0.11 mmol). The resulting mixture was stirred at -15° C. for 15minutes. Subsequently, a solution of13-O-(3-amino-2-hydroxy-3-phenylpropionyl)-7,10-bis-O-(212,2-trichloroethoxycarbonyl)-10-deacetylbaccatinIII (106 mg, 0.10 mmol) in tetrahydrofuran (10 ml) was slowly added.After the thus-obtained mixture was stirred for 1 hour, they werereacted at room temperature for 14 hours. Water was added to thereaction mixture, followed by extraction with chloroform. The organiclayer was washed with a saturated aqueous solution of sodiumhydrogencarbonate, dried over anhydrous magnesium sulfate, and thenconcentrated to dryness under reduced pressure. The residue was purifiedby chromatography on a silica gel column (chloroform-methanol mixedsolvent [19:1]). Eluted TLC single-spot fractions were combined togetherand then concentrated to dryness under reduced pressure, whereby thetitle compound (24 mg, 18%) was obtained as a colorless oil.

¹ H-NMR (CDCl₃)δ: 1.18(3H,s,C-16 or C17-Me), 1.22(3H,s,C-16 or C17-Me),1.45-1.66(8H,m), 1.86(3H,s,C19-Me), 1.85-1.97(3H,m), 1.90(3H,s,C18-Me),2.07(1H,m), 2.31(2H,m), 2.40(3H,s,C4-OAc), 2.50-2.65(6H,m), 2.81(1H,m),2.95(1H,m), 3.64(1H,s), 3.89(1H,d,J=7 Hz,C3-H), 4.20(1H,d,J=8 Hz,C20-H),4.32(1H,d,J=9 Hz,C20-H), 4.18-4.33(2H,m), 4.60(1H,d,J=12 Hz,Troc),4.77(2H,s,Troc), 4.79(1H,d,J=2 Hz,C2'-H), 4.91(1H,d,J=12 Hz,Troc),4.95(1H,d,J=8 Hz,C5-H), 5.53(1H,dd,J=8,11 Hz,C7-H), 5.69(1H,d,J=11Hz,C2-H), 5.78(1H,d,J=9 Hz,C3'-H), 6.20(1H,t,C13-H), 6.21(1H,s,C10-H),7.09(2H,d,J=9 Hz,ArH), 7.20(1H,m), 7.34-7.62(8H,m,ArH), 7.75(2H,d,J=9Hz,ArH), 8.12(2H,d,J=7 Hz,ArH).

Example 67

13-O-[2-Hydroxy-3-phenyl-3-{4-(4-piperidinopiperidinocarbonyloxy)benzoylamino}propionyl]-10-deacetylbaccatinIII (Compound 68)

The compound (20 mg, 0.014 mmol) of Example 66 was dissolved in aceticacid-methanol (1:1) mixed solvent (2 ml), followed by the addition ofzinc powder (13 mg). The resulting mixture was stirred at 90° C. for 8hours. A precipitate in the reaction mixture was filtered off and waterwas added to the filtrate. The resulting mixture was extracted withchloroform. The organic layer was washed with a saturated aqueoussolution of sodium hydrogencarbonate and a saturated aqueous solution ofsodium chloride, dried over anhydrous magnesium sulfate, and thenconcentrated to dryness under reduced pressure. The residue was purifiedby chromatography on a silica gel column (chloroform-methanol mixedsolvent [19:1]). Eluted TLC single-spot fractions were combined togetherand then concentrated to dryness under reduced pressure, whereby thetitle compound (6 mg, 40%) was obtained as colorless crystals.

¹ H-NMR (CDCl₃)δ: 1.07(3H,s,C-16 or C17-Me), 1.16(3H,s,C-16 or C17-Me),1.20-1.26(1H,m), 1.73(6H,s,C18-Me and C19-Me), 1.52-1.90(11H,m),2.03-2.31(4H,m), 2.39(3H,s,C4-OAc), 2.52(1H,m), 2.77(1H,m), 2.90(1H,m),3.62(1H,s), 3.85(1H,d,J=7 Hz,C3-H), 4.20(1H,d,J=8 Hz,C20-H),4.28(1H,d,J=9 Hz,C20-H), 4.40(1H,m), 4.75(1H,s,C2'-H), 4.91(1H,d,J=10Hz,C5-H), 5.15(1H,s,C10-H), 5.63(1H,d,J=7 Hz,C2-H), 5.78(1H,d,J=9Hz,C3'-H), 6.17(1H,t,C13-H), 7.08(2H,d,J=9 Hz,ArH), 7.24-7.59(8H,m,ArH),7.84(2H,d,J=8 Hz,ArH), 8.10(2H,d,J=8 Hz,ArH). SI-MS m/z: 1022 [M+H]⁺

Example 68

13-O-[3-(4-Benzyloxycarbonylpiperazinocarbonylamino)-2-hydroxy-3-phenylpropionyl]-7-O-triethylsilylbaccatinIII (Compound 69)

Using 4-benzyloxycarbonylpiperazinocarbonyl chloride (33 mg, 0.12 mmol),the title compound (27 mg, 25%) was obtained as a yellow solid byconducting a reaction and post-treatment as in Example 52.

¹ H-NMR (CDCl₃)δ: 0.50-0.64(6H,m,Si--CH₂ CH₃ X3), 0.91(9H,t,J=8Hz,Si--CH₂ CH₃ X3), 1.19(3H,s,C-16 or C-17), 1.23(3H,s,C-16 or C-17),1.68-1.78(1H,br), 1.69(3H,s,C-19), 1.83-1.97(1H,m,C-6a), 1.89(3H,d,J=1Hz,C-18), 2.14-2.32(2H,m,C-14), 2.18(3H,s,C-10:OCOCH₃),2.35(3H,s,C-4:OCOCH₃), 2.45-2.57(1H,m,C-6b), 3.20-3.58(8H,m,piperazine),3.78(1H,d,J=7 Hz,C-3), 4.16(1H,d,J=8 Hz,C-20a), 4.29(1H,d,J=8 Hz,C-20b),4.43(1H,dd,J=7,11 Hz,C-7), 4.68(1H,d,J=3 Hz,C-21), 4.91(1H,dd,J=2,9Hz,C-5), 5.12(2H,s,--CH₂ Ph), 5.40(1H,d,J=9 Hz,CONH), 5.47(1H,dd,J=3,9Hz,C-3'), 5.67(1H,d,J=7 Hz,C-2), 6.16(1H,m,C-13), 6.42(1H,s,C-10),7.27-7.64(13H,m,C-3'-Ph,C-2-Bz(m,p) and --CH₂ Ph), 8.10(2H,dd,J=1,8Hz,C-2-Bz(o)).

Example 69

13-O-[2-Hydroxy-3-phenyl-3-(piperazinocarbonylamino)propionyl]baccatinIII (Compound 70)

The compound (41 mg, 0.037 mmol) of Example 68 was dissolved in methanol(10 ml), followed by the addition of 10% palladium on charcoal (10 mg).The resulting mixture was vigorously stirred at room temperature for 5.5hours under a hydrogen gas atmosphere. The catalyst was filtered off andthe filtrate was then concentrated to dryness under reduced pressure,whereby a colorless solid (38 mg) was obtained. The thus-obtainedcolorless solid was dissolved in ethanol (3.8 ml), followed by theaddition of 0.1 N hydrochloric acid (3.8 ml) at 0° C. under stirring.The thus-obtained mixture was stirred for 3 days. Post-treatment andpurification were conducted as in Example 53, whereby the title compound(21 mg, 68%) was obtained as a colorless solid.

¹ H-NMR (CDCl₃)δ: 1.13(3H,s,C-16 or C-17), 1.25(3H,s,C-16 or C-17),1.67(3H,s,C-19), 1.80-1.92(1H,m,C-6a), 1.79(3H,s,C-18),2.10-2.30(2H,m,C-14), 2.23(3H,s,C-10:OCOCH₃), 2.36(3H,s,C-4:OCOCH₃),2.47-2.58(1H,m,C-6b), 2.79(4H,br-s,piperazine), 2.80-5.60(1H,br),3.34(4H,m,piperazine), 3.77(1H,d,J=7 Hz,C-3), 4.16(1H,d,J=8 Hz,C-20a),4.27(1H,d,J=8 Hz,C-20b), 4.39(1H,dd,J=7,11 Hz,C-7), 4.67(1H,d,J=3Hz,C-2'), 4.93(1H,dd,J=1,9 Hz,C-5), 5.43(1H,dd,J=3,8 Hz,C-3'),5.49(1H,br), 5.65(1H,d,J=7 Hz,C-2), 6.20(1H,br-t,J=9 Hz,C-13),6.27(1H,s,C-10), 7.25-7.65(8H,m,C-31-Ph and C-2-Bz(m,p)),8.10(2H,dd,J=1,8 Hz,C-2-Bz(o)). SI-MS m/z: 862 [M+H]⁺

Example 70

13-O-[2-Hydroxy-3-(4-methylpiperazinocarbonylamino)-3-phenylpropionyl]-7-O-triethylsilylbaccatinIII (Compound 71)

Using 4-methylpiperazinocarbonyl chloride (19 mg, 0.12 mmol), the titlecompound (16 mg, 17%) was obtained as a pale yellow solid by conductinga reaction and post-treatment as in Example 52.

¹ H-NMR (CDCl₃)δ: 0.50-0.64(6H,m,Si--CH₂ CH₃ X3), 0.92(9H,t,J=8Hz,Si--CH₂ CH₃ X3), 1.20(3H,s,C-16 or C-17), 1.23(3H,s,C-16 or C-17),1.69(3H,s,C-19), 1.78(1H,br-s), 1.83-1.94(1H,m,C-6a), 1.91(3H,d,J=1Hz,C-18), 2.13-2.40(6H,br-m,C-14,pip-CH₂ X2), 2.18(3H,s,C-10:OCOCH₃),2.27(3H,s,N--CH₃), 2.36(3H,s,C-4:OCOCH₃), 2.45-2.57(1H,m,C-6b),3.25-3.50(4H,br-m,pip-CH₂ X2), 3.79(1H,d,J=7 Hz,C-3), 4.16(1H,d,J=8Hz,C-20a), 4.28(1H,d,J=8 Hz,C-20b), 4.44(1H,dd,J=7,11 Hz,C-7),4.67(1H,d,J=3 Hz,C-2'), 4.91(1H,dd,J=2,9 Hz,C-5), 5.39(1H,d,J=9Hz,CONH), 5.46(1H,dd,J=3,9 Hz,C-31), 5.67(1H,d,J=7 Hz,C-2),6.16(1H,br-t,J=9 Hz,C-13), 6.42(1H,s,C-10), 7.26-7.64(8H,m,C-31-Ph andC-2-Bz(m,p)), 8.10(2H,dd,J=2,9 Hz,C-2-Bz(o)).

Example 71

13-O-[2-Hydroxy-3-(4-methylpiperazinocarbonylamino)-3-phenylpropionyl]baccatinIII (Compound 72)

The compound (16 mg, 0.016 mmol) of Example 70 was dissolved in ethanol(1.6 ml), followed by the addition of 0.1 N hydrochloric acid (1.6 ml)at 0° C. under stirring. The resulting mixture was stirred for 4 days.Post-treatment and purification were conducted as in Example 53, wherebythe title compound (11 mg, 78%) was obtained as a colorless solid.

¹ H-NMR (CDCl₃)δ: 1.14(3H,s,C-16 or C-17), 1.26(3H,s,C-16 or C-17),1.67(3H,s,C-19), 1.79(3H,s,C-18), 1.80-1.92(1H,m,C-6a),2.13-2.43(6H,m,C-14,pip-CH₂ X2), 2.24(3H,s,C-10:OCOCH₃),2.28(3H,s,N--CH₃), 2.37(3H,s,C-4:OCOCH₃), 2.48-2.59(1H,m,C-6b),3.26-3.50(4H,m,pip-CH₂ X2), 3.77(1H,d,J=7 Hz,C-3), 4.16(1H,d,J=8Hz,C-20a), 4.28(1H,d,J=8 Hz,C-20b), 4.40(1H,dd,J=7,11 Hz,C-7),4.67(1H,d,J=3 Hz,C-2'), 4.93(1H,dd,J=2,10 Hz,C-5), 5.39(1H,J=8 Hz,CONH),5.44(1H,dd,J=3,8 Hz,C-31), 5.65(1H,d,J=7 Hz,C-2), 6.20(1H,br-t,J=9Hz,C-13), 6.27(1H,s,C-10), 7.25-7.70(8H,m,C-3'-Ph and C-2-Bz(m,p)),8.10(2H,dd,J=2,9 Hz,C-2-Bz(o)). SI-MS m/z: 876 [M+H]⁺

Example 72

13-O-[3-(4-Ethylpiperazinocarbonylamino)-2-hydroxy-3-phenylpropionyl]-7-O-triethylsilylbaccatinIII (Compound 73)

Using 4-ethylpiperazinocarbonyl chloride (19 mg, 0.11 mmol), the titlecompound (15 mg, 16%) was obtained as a colorless solid by conducting areaction and post-treatment as in Example 52.

¹ H-NMR (CDCl₃)δ: 0.50-0.64(6H,m,Si--CH₂ X3), 0.92(9H,t,J=8 Hz,Si--Ch₂CH₃ X3), 1.07(3H,t,J=7 Hz,N--CH₂ CH₃), 1.20(3H,s,C-16 or C-17),1.23(3H,s,C-16 or C-17), 1.69(3H,s,C-19), 1.76(1H,s,C-1:OH),1.83-1.94(1H,m,C-6a), 1.91(3H,d,J=1 Hz,C-18),2.16-2.58(9H,m,C-14,pip-CH₂ X2,N--CH₂ CH₃ and C-6b),2.18(3H,s,C-10:OCOCH₃), 2.37(3H,s,C-4:OCOCH₃), 3.25-3.50(4H,m,pip-CH₂X2), 3.79(1H,d,J=7 Hz,C-3), 4.16(1H,d,J=8 Hz,C-20a), 4.28(1H,d,J=8Hz,C-20b), 4.44(1H,dd,J=7,11 Hz,C-7), 4.68(1H,d,J=3 Hz,C-2'),4.91(1H,dd,J=2,10 Hz,C-5), 5.41(1H,br-d,J=9 Hz,CONH), 5.46(1H,dd,J=3,9Hz,C-31), 5.67(1H,d,J=7 Hz,C-2), 6.17(1H,br-t,J=9 Hz,C-13),6.42(1H,s,C-10), 7.27-7.64(8H,m,C-3'-Ph and C-2-Bz(m,p)),8.10(2H,dd,J=2,9 Hz,C-2-Bz(o)).

Example 73

13-O-[3-(4-Ethylpiperazinocarbonylamino)-2-hydroxy-3-phenylpropionyl]baccatinIII (Compound 74)

The compound (15 mg, 0.019 mmol) of Example 72 was dissolved in ethanol(2 ml), followed by the addition of 0.1 N hydrochloric acid (2 ml) at 0°C. under stirring. The resulting mixture was stirred for 4 days.Post-treatment was conducted as in Example 531 whereby the titlecompound (11 mg, 85%) was obtained as a colorless solid.

¹ H-NMR (CDCl₃)δ: 1.07(3H,t,J=7 Hz,N--CH₂ CH₃), 1.14(3H,s,C-16 or C-17),1.26(3H,s,C-16 or C-17), 1.67(3H,s,C-19), 1.79(3H,d,J=1 Hz,C-18),1.81-1.92(1H,m,C-6a), 2.13-2.60(9H,m,C-14,pip-CH₂ X2,N--CH₂ CH₃ andC-6b), 2.25(3H,s,C-10:OCOCH₃), 2.38(3H,s,C-4:OCOCH₃),3.30-3.50(4H,m,pip-CH₂ X2), 3.78(1H,d,J=7 Hz,C-3), 4.17(1H,d,J=8Hz,C-20a), 4.29(1H,d,J=8 Hz,C-20b), 4.40(1H,dd,J=7,11 Hz,C-7),4.67(1H,d,J=3 Hz,C-2'), 4.94(1H,dd,J=2,10 Hz,C-5), 5.37(1H,br-d,J=8Hz,CONH), 5.44(1H,dd,J=3,8 Hz,C-31), 5.66(1H,d,J=7 Hz,C-2),6.21(1H,br-t,J=9 Hz,C-13), 6.27(1H,s,C-10), 7.27-7.43(5H,m,C-31-Ph),7.47-7.65(3H,m,C-2-Bz(m,p)), 8.11(2H,dd,J=2,9 Hz,C-2-Bz(o)). SI-MS m/z:890 [M+H]⁺

Example 74

13-O-[2-Hydroxy-3-(4-(isopropylaminocarbonylmethyl)piperazinocarbonylamino)-3-phenylpropionyl]-7,10-bis-O-(2,2,2-trichloroethoxycarbonyl)-10-deacetylbaccatinIII (Compound 75)

13-O-(3-Amino-2-hydroxy-3-phenylpropionyl)-7,10-bis-O-(2,2,2-trichloroethoxycarbonyl)-10-deacetylbaccatinIII (106 mg, 0.10 mmol) and4-(isopropylaminocarbonylmethyl)piperazinocarbonyl chloride (27 mg, 0.11mmol) were dissolved in tetrahydrofuran (10 ml), followed by theaddition of triethylamine (11 mg, 0.11 mmol). The resulting mixture wasstirred at room temperature for 15 hours. The reaction mixture wasconcentrated to dryness under reduced pressure. The residue was purifiedby chromatography on a silica gel column (chloroform-methanol mixedsolvent [29:1]). Eluted TLC single-spot fractions were combined togetherand then concentrated to dryness under reduced pressure, whereby thetitle compound (48 mg, 20%) was obtained as colorless crystals.

¹ H-NMR (CDCl₃)δ: 1.12(3H,s,isopropyl-Me), 1.14(3H,s,isopropyl-Me),1.19(3H,s,C-16 or C17-Me), 1.26(3H,s,C-16 or C17-Me), 1.85(3H,s,C19-Me),1.89(3H,s,C18-Me), 2.01-2.03(1H,m), 2.27(2H,m), 2.39(3H,s,C4-OAc),2.39-2.45(4H,m,Piperazine-H), 2.61(1H,m,C6-H), 2.93(2H,s,CH₂),3.35-3.39(4H,m,Piperazine-H), 3.89(1H,d,J=7 Hz,C3-H),4.06(1H,m,isopropyl-CH), 4.17(1H,d,J=9 Hz,C20-H), 4.31(1H,d,J=9Hz,C20-H), 4.61(1H,d,J=12 Hz,Troc), 4.69(1H,d,J=3 Hz,C2'-H),4.78(2H,s,Troc), 4.90(1H,d,J=12 Hz,Troc), 4.94(1H,d,J=8 Hz,C5-H),5.47(1H,m,C7-H), 5.53(1H,m,C3'-H), 5.68(1H,d,J=7 Hz,C2-H), 6.20(1H,t,J=8Hz,C13-H), 6.22(1H,s), 6.77(1H,d,J=9 Hz,NH), 7.31-7.66(5H,m,ArH),7.45-7.53(2H,m,ArH), 7.48-7.68(1H,m,ArH), 8.08-8.10(2H,m,ArH).

Example 75

13-O-[2-Hydroxy-3-{4-(isopropylaminocarbonylmethyl)piperazinocarbonylamino}-3-phenylpropionyl]-10-deacetylbaccatinIII (Compound 76)

The compound (48 mg, 0.038 mmol) of Example 74 was dissolved in aceticacid-methanol (1:1) mixed solvent (2 ml), followed by the addition ofzinc powder (50 mg). The resulting mixture was stirred at 60° C. for 2.5hours. A precipitate in the reaction mixture was filtered off, and waterwas added to the filtrate. The thus-obtained mixture was extracted withchloroform. The organic layer was washed with a saturated aqueoussolution of sodium hydrogencarbonate and a saturated aqueous solution ofsodium chloride, dried over anhydrous magnesium sulfate, and thenconcentrated to dryness under reduced pressure. The residue was purifiedby chromatography on a silica gel column (chloroform-methanol mixedsolvent [19:1]). Eluted TLC single-spot fractions were combined togetherand then concentrated to dryness under reduced pressure, whereby thetitle compound (20 mg, 60%) was obtained as colorless crystals.

¹ H-NMR (CDCl₃)δ: 1.11(3H,s,C-16 or C17-Me), 1.12(3H,s,isopropyl-Me),1.14(3H,s,isopropyl-Me), 1.22(3H,s,C-16 or C17-Me), 1.73(3H,s,C19-Me),1.79(3H,s,C18-Me), 1.82-1.90(2H,m), 2.03(1H,s), 2.19-2.26(2H,m),2.36(3H,s,C4-OAc), 2.39-2.45(4H,m,Piperazine-H), 2.52(1H,m,C6-H),2.94(2H,s,isopropyl-CH₂), 3.35-3.43(4H,m,Piperazine-H), 3.85(1H,d,J=7Hz,C3-H), 4.06(1H,m,CH), 4.17(1H,d,J=8 Hz,C20-H), 4.22(1H,br),4.29(1H,d,J=8 Hz,C20-H), 4.34(1H,br), 4.67(1H,d,J=3 Hz,C2'-H),4.92(1H,d,J=8 Hz,C5-H), 5.21(1H,s,C10-H), 5.43(1H,dd,J=3,8 Hz,C3'-H),5.64(1H,d,J=7 Hz,C2-H), 5.66(1H,s), 6.18(1H,t,J=8 Hz,C13-H),6.79(1H,d,J=9 Hz,NH), 7.24-7.60(8H,m,ArH), 8.09(2H,d,J=7 Hz,ArH). SI-MSm/z: 919 [M+H]⁺

Example 76

13-O-[2-Hydroxy-3-{3-(4-isopropylaminocarbonylmethylpiperazinocarbonyl)propionylamino}-3-phenylpropionyl]-7-O-triethylsilylbaccatinIII (Compound 77)

Using 3-(4-isopropylaminocarbonylmethylpiperazinocarbonyl)propionic acid(33 mg, 0.12 mmol), the title compound (25 mg, 23%) was obtained as acolorless solid by conducting a reaction and post-treatment as inExample 62.

¹ H-NMR (CDCl₃)δ: 0.49-0.65(6H,m,Si--CH₂ X3), 0.92(9H,t,J=8 Hz,Si--CH₂CH₃ X3), 1.17(6H,d,J=6 Hz,--CH(CH₃)₂), 1.23(3H,s,C-16 or C-17),1.24(3H,s,C-16 or C-17), 1.70(3H,s,C-19), 1.82-1.95(1H,m),2.00(3H,s,C-18), 2.13-2.74(10H,m), 2.19(3H,s,C-10:OCOCH₃),2.39(3H,s,C-4:OCOCH₃), 2.80-3.14(3H,m), 2.86(2H,s,--COCH₂ N═),3.20-3.30(1H,br-m), 3.44-3.56(1H,br-m), 3.80(1H,d,J=7 Hz,C-3),4.01-4.15(1H,m,--CH(CH₃)₂), 4.22(2H,s,C-20), 4.46(1H,dd,J=7,11 Hz,C-7),4.67(1H,br-s,C-2'), 4.91(1H,dd,J=1,9 Hz,C-5), 5.61(1H,dd,J=2,9 Hz,C-3'),5.68(1H,d,J=7 Hz,C-2), 6.29(1H,br-t,J=9 Hz,C-13), 6.42(1H,s,C-10),6.71(1H,br-d,J=9 Hz), 6.89(1H,br-d,J=9 Hz), 7.27-7.63(8H,m,C-3'-Ph andC-2-Bz(m,p)), 8.13(2H,dd,J=1,9 Hz,C-2-Bz(o)).

Example 77

13-O-[2-Hydroxy-3-{3-(4-isopropylaminocarbonylmethylpiperazinocarbonyl)propionylamino}-3-phenylpropionyl]baccatinIII (Compound 78)

The compound (25 mg, 0.022 mmol) of Example 66 was dissolved in ethanol(2.5 ml), followed by the addition of 0.1 N hydrochloric acid (2.5 ml)at 0° C. under stirring. The resulting mixture was stirred for 4 days.Post-treatment and purification were conducted as in Example 53, wherebythe title compound (20 mg, 90%) was obtained as a colorless solid.

¹ H-NMR (CDCl₃)δ: 1.16(3H,s,C-16 or C-17), 1.17(6H,d,J=7 Hz,--CH(CH₃)₂),1.30(3H,s,C-16 or C-17), 1.69(3H,s,C-19), 1.82-1.94(1H,m), 1.88(3H,d,J=1Hz,C-18), 2.19-2.74(11H,m), 2.24(3H,s,C-10:OCOCH₃),2.40(3H,s,C-4:OCOCH₃), 2.87(2H,s,--COCH₂ N═), 2.91-3.29(4H,m),3.40-3.51(1H,br-m), 3.73-3.96(1H,br), 3.79(1H,d,J=7 Hz,C-3),4.00-4.15(1H,m,--CH(CH₃)₂), 4.21(1H,d,J=9 Hz,C-20a), 4.25(1H,d,J=9Hz,C-20b), 4.40(1H,br-t,J=8 Hz,C-7), 4.67(1H,d,J=2 Hz,c-2'),4.92(1H,dd,J=2,10 Hz,C-5), 5.61(1H,dd,J=2,9 Hz,C-31), 5.67(1H,d,J=7Hz,C-2), 6.29(1H,s,C-10), 6.34(1H,br-t,J=9 Hz,C-13), 6.70(1H,br-d,J=8Hz), 6.84(1H,d,J=9 Hz), 7.29-7.43(5H,m,c-3'-Ph),7.48-7.63(3H,m,C-2-Bz(m,p)), 8.13(2H,dd,J=2,9 Hz,C-2-Bz(o)). SI-MS m/z:1017 [M+H]⁺

Example 78

13-O-[2-Hydroxy-3-{(4-isopropylaminocarbonylmethylpiperazinocarbonyloxy)acetylamino}-3-phenylpropionyl]-7-O-triethylsilylbaccatinIII (Compound 79)

Using (4-isopropylaminocarbonylmethylpiperazinocarbonyloxy)acetic acid(33 mg, 0.12 mmol), the title compound (39 mg, 35%) was obtained as acolorless solid by conducting a reaction and post-treatment as inExample 62.

¹ H-NMR (CDCl₃)δ: 0.42-0.59(6H,m,Si--CH₂ CH₃ X3), 0.85(9H,t,J=8Hz,Si--CH₂ CH₃ X3), 1.07(3H,d,J=6 Hz,--CH(CH₃)₂), 1.08(3H,d,J=6Hz,--CH(CH₃)₂), 1.15(3H,s,C-16 or C-17), 1.17(3H,s,C-16 or C-17),1.63(3H,s,C-19), 1.77-1.98(1H,m), 1.84(3H,s,C-18), 2.08-2.50(8H,m),2.11(3H,s,C-10:OCOCH₃), 2.32(3H,s,C-4:OCOCH₃), 2.83(2H,s,--COCH₂ N═),2.97-3.58(4H,br-m), 3.71(1H,d,J=7 Hz,C-3), 3.92-4.05(1H,m,--CH(CH₃)₂),4.15(1H,d,J=7 Hz,C-20a), 4.18(1H,d,J=7 Hz,C-20b), 4.36(1H,dd,J=7,11Hz,C-7), 4.43(1H,d,J=15 Hz,--COOCH(H)CONH--), 4.56(1H,d,J=15Hz,--COOCH(H)CONH--), 4.66(1H,d,J=2 Hz,C-2'), 4.83(1H,d,J=8 Hz,C-5),5.57(1H,dd,J=2,9 Hz,C-3'), 5.61(1H,d,J=7 Hz,C-2), 6.17(1H,br-t,J=9Hz,c-13), 6.34(1H,s,C-10), 6.65(1H,br-d,J=7 Hz), 6.88(1H,d,J=9 Hz),7.20-7.59(8H,m,C-3'-Ph and C-2-Bz(m,p)), 8.05(2H,d,J=7 Hz,C-2-Bz(o)).

Example 79

13-O-[2-Hydroxy-3-{(4-isopropylaminocarbonylmethylpiperazinocarbonyloxy)acetylamino}-3-phenylpropionyl]baccatinIII (Compound 80)

The compound (39 mg, 0.034 mmol) of Example 78 was dissolved in ethanol(3.9 ml), followed by the addition of 0.1 N hydrochloric acid (3.9 ml)at 0° C. under stirring. The resulting mixture was stirred for 4 days.Post-treatment and purification were conducted as in Example 53, wherebythe title compound (30 mg, 87%) was obtained as a colorless solid.

¹ H-NMR (CDCl₃)δ: 1.15(3H,d,J=7 Hz,--CH(CH₃)₂), 1.16(3H,d,J=7Hz,--CH(CH₃)₂), 1.17(3H,s,C-16 or C-17), 1.28(3H,s,C-16 or C-17),1.69(3H,s,C-19), 1.88(3H,d,J=1 Hz,C-18), 1.83-1.93(1H,m),2.24(3H,s,C-10:OCOCH₃), 2.25-2.44(6H,m), 2.39(3H,s,C-4:OCOCH₃),2.48-2.63(2H,m), 2.68(1Hfs), 2.90(2H,s,--COCH₂ N═), 3.00-3.58(4H,m),3.78(1H,d,J=7 Hz,C-3), 4.00-4.11(1H,m,--CH(CH₃)₂), 4.25(2H,s,C-20),4.39(1H,br-m,C-7), 4.49(1H,d,J=15 Hz,--COOCH(H)CONH--), 4.63(1H,d,J=15Hz,--COOCH(H)CONH--), 4.74(1H,d,J=2 Hz,C-2'), 4.92(1H,dd,J=2,10Hz,C-5),5.65(1H,dd,J=2,10 Hz,C-3'), 5.68(1H,d,J=7 Hz,C-2), 6.28(1H,s,C-10),6.30(1H,br-t,J=8 Hz,C-13), 6.71(1H,br-d,J=7 Hz), 6.91(1H,d,J=9 Hz),7.30-7.64(8H,m,C-3'-Ph and C-2-Bz(m,p)), 8.13(2H,dd,J=2,9 Hz,C-2-Bz(o)).SI-MS m/z: 1019 [M+H]⁺

Alternative Synthesis Process for Compound 80

Formic acid (3 ml) was added to13-O-[3-(tert-butoxycarbonyl)-2,2-dimethyl-4-phenyl-5-oxazolidinecarbonyl]-7-O-triethylsilylbaccatinIII (0.07 g, 0.07 mmol). The resulting mixture was stirred at roomtemperature for 3 hours. Subsequent to confirmation of full consumptionof the raw material by TLC, chloroform was added to the reactionmixture, and the thus-obtained mixture was washed with a saturatedaqueous solution of sodium hydrogencarbonate. The organic layer wasdried over anhydrous magnesium sulfate and the solvent was distilled offunder reduced pressure. The residue was dissolved in methylene chloride,followed by the addition of[4-(isopropylaminocarbonylmethyl)piperazinocarbonyloxy]acetic acid (32mg, 0.11 mmol) and DCC (23 mg, 0.11 mmol). The resulting mixture wasstirred under reflux for 20 hours. The reaction mixture was filtered.After the filtrate was concentrated, chloroform was added. Thethus-obtained mixture was washed with a saturated aqueous solution ofsodium hydrogencarbonate. The organic layer was dried over anhydrousmagnesium sulfate and the solvent was distilled off under reducedpressure. The residue was preliminarily purified by chromatography on asilica gel column (chloroform-methanol mixed solvent [97:3→19:1]).Further purification was conducted by reverse-phase high-performanceliquid column chromatography (eluent: acetonitrile-water mixed solvent[1:1], whereby the title compound (5 mg, 7%) was obtained.

Example 80

13-O-[2-Hydroxy-3-phenyl-3-(N,N,N'-trimethylethylenediaminocarbonylamino)propionyl]-7-O-triethylsilylbaccatinIII (Compound 81)

13-O-(3-Amino-2-hydroxy-3-phenylpropionyl)-7-O-triethylsilylbaccatin III(57 mg, 0.07 mmol), which had been prepared by conducting a reaction andpost-treatment as in Example 52, was dissolved in dry pyridine (20 ml),to which N,N,N'-trimethylethylenediaminocarbonyl chloride hydrochloride(20 mg, 0.10 mmol) and triethylamine (14 at, 0.1 mmol) were added. Theresulting mixture was stirred at 50° C. for 2 days. Carbonyl chlorideand triethylamine were added further, and were reacted likewise. Aprecipitate was filtered off, and the solvent was distilled off underreduced pressure. The residue was purified by chromatography on an ODScolumn (eluent: 10 mM potassium dihydrogenphosphate-acetonitrile mixedsolvent [1:2], detection: 225 nm). Fractions containing the targetcompound were combined together, followed by the addition of chloroformand a 7% aqueous solution of sodium hydrogencarbonate. The thus-obtainedmixture was allowed to separate into layers. The chloroform layer waswashed with a saturated aqueous solution of sodium chloride, dried overanhydrous sodium sulfate, and then concentrated to dryness under reducedpressure, thereby the title compound (8 mg, 12%) was obtained as acolorless solid.

¹ H-NMR (CDCl₃)δ: 0.50-0.65(6H,m,Si--CH₂ X3), 0.92(9H,t,J=8 Hz,Si--CH₂CH₃ X3), 1.20(3H,s,C-16 or C-17), 1.26(3H,s,C-16 or C-17),1.68(3H,s,C-19), 1.82-1.92(1H,m,C-6a), 1.97(3H,s,C-18),2.18(3H,s,C-10:OCOCH₃), 2.22-2.38(2H,m,C-14), 2.32(3H,s,C-4:OCOCH₃),2.45-2.55(1H,m,C-6b), 2.68(6H,br-s,N(CH₃)₂), 2.94-3.14(2H,br-m),3.02(3H,s,CONCH₃), 3.28-3.36(1H,br-m), 3.80(1H,d,J=7 Hz,C-3),4.00-4.12(1H,br-m), 4.15(1H,d,J=8 Hz,C-20a), 4.27(1H,d,J=8 Hz,C-20b),4.45(1H,dd,J=7,10 Hz,C-7), 4.67(1H,d,J=3 Hz,C-2'),4.91(1H,dd,J=1,10Hz,C-5), 5.40(1H,dd,J=3,9 Hz,C-3'), 5.67(1H,d,J=7Hz,C-2), 5.98(1H,br,CONH), 6.17(1H,br-t,J=9 Hz,C-13), 6.43(1H,s,C-10),7.25-7.65(8H,m,C-31-Ph and C-2-Bz(m,p)), 8.12(2H,dd,J=1,9 Hz,C-2-Bz(o)).

Example 81

13-O-[2-Hydroxy-3-phenyl-3-(N,N,N'-trimethylethylenediaminocarbonylamino)propionyl]baccatinIII (Compound 82)

The compound (8 mg, 0.008 mmol) of Example 80 was dissolved in ethanol(0.8 ml), followed by the addition of 0.1 N hydrochloric acid (0.8 ml)at 0° C. under stirring. The resulting mixture was stirred for 4 days.Post-treatment and purification were conducted as in Example 53, wherebythe title compound (1 mg, 16%) was obtained as a slightly yellow solid.

¹ H-NMR (CDCl₃)δ: 1.21(3H,s,C-16 or C-17), 1.23(3H,s,C-16 or C-17),1.70(3H,s,C-19), 1.80-1.90(1H,m,C-6a), 1.97(3H,d,J=1 Hz,C-18),2.04-2.15(2H,m,C-14), 2.22(3H,s,C-10:OCOCH₃), 2.40(3H,s,C-4:OCOCH₃),2.47-2.54(1H,m,C-6b), 3.01(3H,s,CONCH₃), 3.39(6H,s,N(CH₃)₂),3.69(2H,br-s), 3.88(1H,d,J=7 Hz,C-3), 4.05(1H,dd,J=2,6 Hz),4.23(2H,s,C-20), 4.26(1H,dd,J=2,6 Hz), 4.37(1H,dd,J=7,11 Hz,C-7),4.66(1H,d,J=5 Hz,C-2'), 5.04(1H,dd,J=2,10Hz,C-5), 5.34-5.42(2H,m,C-3'and CONH), 5.70(1H,d,J=7 Hz,C-2), 6.21(1H,br-t,J=9 Hz,C-13),6.51(1H,s,C-10, 7.27-7.80(8H,m,C-31-Ph and C-2-Bz(m,p)),8.15(2H,dd,J=1,9 Hz,C-2-Bz(o)). SI-MS m/z: 878 [M+H]⁺

Compounds 53-82 obtained above in Examples 52-81 are shown in thefollowing Tables 8-12.

                                      TABLE 8                                     __________________________________________________________________________     ##STR84##                                                                    Comp'd No.                                                                          B--A--                   Y   Z                                          __________________________________________________________________________    53                                                                                   ##STR85##               Ac  TES                                        55                                                                                   ##STR86##               Ac  TES                                        57                                                                                   ##STR87##               Ac  TES                                        59                                                                                   ##STR88##               Ac  TES                                        61                                                                                   ##STR89##               Ac  TES                                        63                                                                                   ##STR90##               Ac  TES                                        67                                                                                   ##STR91##               Troc                                                                              Troc                                       69                                                                                   ##STR92##               Ac  TES                                        __________________________________________________________________________

                  TABLE 9                                                         ______________________________________                                         ##STR93##                                                                    Comp'd No.                                                                              B--A--             Y     Z                                          ______________________________________                                        71                                                                                       ##STR94##         Ac    TES                                        73                                                                                       ##STR95##         Ac    TES                                        ______________________________________                                    

                  TABLE 10                                                        ______________________________________                                         ##STR96##                                                                    Comp'd No.                                                                            B--A--                  Y      Z                                      ______________________________________                                        54                                                                                     ##STR97##              Ac     H                                      56                                                                                     ##STR98##              Ac     H                                      58                                                                                     ##STR99##              Ac     H                                      60                                                                                     ##STR100##             Ac     H                                      62                                                                                     ##STR101##             Ac     H                                      64                                                                                     ##STR102##             Ac     H                                      65                                                                                     ##STR103##             H      H                                      66                                                                                     ##STR104##             H      H                                      ______________________________________                                    

                                      TABLE 11                                    __________________________________________________________________________     ##STR105##                                                                   Comp'd No.                                                                          B--A--                   Y   Z                                          __________________________________________________________________________    68                                                                                   ##STR106##              H   H                                          79                                                                                   ##STR107##              Ac  H                                          72                                                                                   ##STR108##              Ac  H                                          74                                                                                   ##STR109##              Ac  H                                          76                                                                                   ##STR110##              H   H                                          78                                                                                   ##STR111##              Ac  H                                          80                                                                                   ##STR112##              Ac  H                                          82                                                                                   ##STR113##              Ac  H                                          __________________________________________________________________________

                  TABLE 12                                                        ______________________________________                                         ##STR114##                                                                   Comp'd                                                                        No.   B--A--                   Y      Z                                       ______________________________________                                        75                                                                                   ##STR115##              Troc   Troc                                    77                                                                                   ##STR116##              Ac     TES                                     79                                                                                   ##STR117##              Ac     TES                                     81                                                                                   ##STR118##              Ac     TES                                     ______________________________________                                    

Solubilities of Taxane Derivatives (1) in Water

I) Preparation of calibration curves:

Compounds (3) and (42) were weighed in amounts of 1.16 mg and 0.65 mg,to which acetonitrile was added in amounts of 2.0 ml and 1.30 ml so thatthe compounds were dissolved to provide standard solutions. Using 20 μlportions of the standard solutions, tests were conducted by HPLC(operation conditions 1). Peak areas of the compounds (3) and (42),which had been obtained from chromatograms of their standard solutions,were measured by automated integration. Areas obtained as averages ofthree measurements were plotted against the amounts (11.6 μg and 10.0μg) of the compounds (3) and (42) per 20 μl, whereby calibration curveswere prepared.

Calibration curve for the compound (3): Y=1.2×10⁻⁴ X, calibration curvefor the compound (42): Y=1.19×10⁻⁴ X [X: peak areas, Y: amounts of thecompounds (3) and (42) (μg)]

[HPLC operation conditions 1]

Column: Inertsil ODS-2 (5-250), 40 deg.

Mobile phase: 0.01 M KH₂ PO₄ --CH₃ CN (5:4).

Flow rate: 1.0 ml/min.

Detection: Ultraviolet absorption photometer (225 nm), 0.08AUFS.

II) Solubility tests of the compounds (3) and (42):

The compounds (3) and (42) were weighed in amounts of 3.10 mg and 2.70mg and then suspended in 2.0 ml portions of purified water,respectively. To the respective suspensions, 0.1 N hydrochloric acid wasadded in amounts of 35 λl and 30 μl (1.1 eq.). By ultrasonication theresulting mixtures were formed into uniform suspensions, which were thenshaken at room temperature for 2 hours. The thus-obtained mixtures werefiltered through membrane filters (0.22 pm), and the filtrates wereprovided as test solutions. Using 5 μl portions of the test solutions,tests were conducted by HPLC (operation conditions 1). From areasobtained as averages of three measurements, the solubilities of thecompounds (3) and (42) were determined.

Area (X) of the compound (3) obtained as an average of threemeasurements: 52570

Dissolved amount (Y) of the compound (3): 6.31 μg/5 μl (1.26 mg/ml)

Area (X) of the compound (42) obtained as an average of threemeasurements: 49558

Dissolved amount (Y) of the compound (42): 5.90 μg/5 μl (1.18 mg/ml)

Measurement of Solubility of Taxol in Water

I) Preparation of calibration curve:

Taxol was weighed in an amount of 1.20 mg, to which acetonitrile wasadded so that Taxol was dissolved to give 20.0 ml precisely, whereby astandard solution was provided. By conducting operations in a similarmanner as in the case of the compound (3), a calibration curve wasprepared. Calibration curve: Y=5.20×10⁻⁵ X [X: peak area, Y: Amount ofTaxol (μg))

II) Solubility test of Taxol:

Taxol was weight in an amount of 3.15 mg and then suspended in 30.0 mlof purified water. By ultra-sonication the suspension was formed into auniform suspension, which was then shaken at room temperature for 2hours. By conducting operations in a similar manner as in the case ofthe compound (3), its solubility was determined (injected amount: 100μl).

Area (X) obtained as an average of three measurements: 677

Dissolved amount (Y) of Taxol: 0.04 μg/100 μl (0. 4 μg/ml)

                  TABLE 13                                                        ______________________________________                                        Compound      Solubility (μg/ml)                                           ______________________________________                                        Taxol            0.4                                                          Compound 3    1260                                                            Compound 42   1180                                                            ______________________________________                                    

Test 2

Solubility of Taxane Derivative (1) in Water

I) Preparation of calibration curves:

Compound (58) was weighed in an amount of 2.50 mg, to which acetonitrilewas added in an amount of 2.5 ml so that the compound was dissolved toprovide a standard solution. Using 20 At of the standard solution, atest was conducted by HPLC (operation conditions 1). A peak area of thecompound (58) obtained from a chromatogram of the standard solution wasmeasured by automated integration. The area obtained as an average ofthree measurements was plotted against the amounts (20 μg) of thecompound (58) per 20 μl, whereby calibration curve was prepared.

Calibration curve: Y=1.10×10⁻⁴ X (X: peak area, Y: amount of compound(58) (μg)].

Operation conditions for the HPLC operation were set as in Test 1.

II) Solubility test of the compound (58):

The compound (58) was weighed in an amount of 4.20 mg and then suspendedin purified water (2.0 ml). To the suspension, 0.1 N hydrochloric acid(47 μl, 1.06 eq.) was added. By ultrasonication the resulting mixturewas formed into a uniform suspension, which was then shaken at roomtemperature for 2 hours. The mixture was filtered through a membranefilter (0.22 pm), and the filtrate was provided as a test solution.Using 5 μl of the test solution, a test was conducted by HPLC (the aboveoperation conditions). From an area obtained as an average of threemeasurements, the solubility of the compound (58) was determined.

Area (X) obtained as an average of three measurements: 71999

Dissolved amount (Y) of the compound (58): 7.95 μg/5 μl (1.59 mg/ml)

The solubility of Taxol in water was measured in a similar manner as inTest 1.

                  TABLE 14                                                        ______________________________________                                        Compound      Solubility (μg/ml)                                           ______________________________________                                        Taxol            0.4                                                          Compound 58   1590                                                            ______________________________________                                    

Test 3

Growth Inhibitory Activities of Taxane Derivatives (1)

Materials and procedures

Cells

As a cell strain KB derived from a human mouth cancer, one purchasedfrom Dainippon Pharmaceutical Co., Ltd. and stored in a lyophilized format The Central Research Center, Yakult Honsha Co., Ltd. was used. InDulbeccols modefied Earglets medium containing 10% fetal bovine serum(product of NISSUI PHARMACEUTICAL CO., LTD.), the KB wasmaintenance-cultured under the following conditions: 5%, CO₂ -air, 37°C.

Drugs

Each compound was used by dissolving it at a concentration of 10 mg/mlin DMSO.

Drug Treatment

(1) KB

On Day-1, cells which were in a logarithmic growth phase were inoculatedat 2,000 cells/100 μl/well on 96-well microtiter plates (Falcon #3072)by using a phenol-red-free culture medium with 10% fetal bovine serumcontained therein (Dulbecco's molefied Eargle's medium (Sigma)), andwere cultured overnight. On Day 0, the compounds each of which had beendiluted to 0.03 to 10,000 ng/ml with the same culture medium were addedin 100 μl aliquots to the individual wells, and the cells were culturedfor 3 days. Three wells were used per each drug concentration. Eachplate was provided with three blank wells containing only the culturemedium and also with eight wells as a drug-untreated control.

XTT Assay

Before use, XTT (Sigma) was dissolved at a concentration of 1 mg/me ineach culture media which as free of serum. Phenodin methosulfate (Sigma)dissolved at a concentration of 5 mM in PBS was added to the resultingsolution at a volume ratio of 1/200. To each well, the solution soprepared was added in an amount of 50 μl per well. Subsequent to culturefor 4 hours, OD was measured at 450 nm by ELISA.

Calculation of 50% Growth Inhibitory Concentration (GI₅₀)

GI₅₀ was calculated by interpolation from a concentration-growthinhibition rate (GIR). GIR was determined in accordance with thefollowing formula: ##EQU1## Bibiography Scudiero D A, et al., CacerRes., 48, 4827-4833, 1988.

1994 Report of The Anticancer Agent Screening Special Committee,"Cancers and Chemotherapy", 21, 1306-1307.

Test results are shown in the following table.

                  TABLE 15                                                        ______________________________________                                        Growth Inhibitory Activity of Taxane Derivatives                              Compound       KB                                                             No.            GI.sub.50 (ng/ml)                                                                       Activity ratio                                       ______________________________________                                         6             0.73      2.7                                                   9             0.78      2.6                                                  39             0.59      3.4                                                  42             0.65      3.1                                                  45             0.86      2.3                                                  Taxol          2.0       1.0                                                  ______________________________________                                    

Capability of Exploitation in Industry

The taxane derivatives according to the present invention have very highsolubility in water, namely, water solubility as high as 1,000 times ormore of Taxol, so that they can be formulated into liquid preparationssuch as injections without using any special solvent. In addition, thereare also excellent in antitumor activities.

We claim:
 1. A taxane derivative represented by the following formula(1): ##STR119## wherein at least one of X and Y represents a group--CO--A--B in which A represents a single bond, a group --R--CO--, agroup --R--OCO-- or a group --R--NHCO--, R representing a lower alkylenegroup or a phenylene group, B represents a group ##STR120## in which R¹represents a hydrogen atom, a substituted or unsubstituted alkyl groupor an aralkyloxycarbonyl group, a group ##STR121## in which R²represents an amino group, a mono or di-alkylamino group, a piperidinogroup, a pyrrolidino group or a morpholino group, or a group ##STR122##in which R³, R⁵ and R⁶ each independently represent a hydrogen atom or alower alkyl group and R⁴ represents a lower alkylene group, and theother represents a hydrogen atom, a lower alkanoyl group, a benzoylgroup, an alkoxycarbonyl group or a trihalogenoalkoxycarbonyl group; Zrepresents a hydrogen atom, a trialkylsilyl group or atrihalogenoalkoxycarbonyl group; Ac represents an acetyl group, Bzrepresents a benzoyl group, and Ph represents a phenyl group; or a saltthereof.
 2. A taxane derivative represented by the following formula(2): ##STR123## wherein A represents a single bond, a group --R--CO--, agroup --R--OCO-- or a group --R--NHCO--, R representing a lower alkylenegroup or a phenylene group, B represents a group ##STR124## in which R¹represents a hydrogen atom, a substituted or unsubstituted alkyl groupor an aralkyloxycarbonyl group, a group ##STR125## in which R²represents an amino group, a mono or di-alkylamino group, a piperidinogroup, a pyrrolidino group or a morpholino group, or a group ##STR126##in which R³, R⁵ and R⁶ each independently represent a hydrogen atom or alower alkyl group and R⁴ represents a lower alkylene group;Z representsa hydrogen atom, a trialkylsilyl group or a trihalogenoalkoxycarbonylgroup; E represents a hydrogen atom or a group ##STR127## wherein R⁷represents a hydrogen atom, an alkoxycarbonyl group or anaralkyloxycarbonyl group, R⁸ and R⁹ each independently represent ahydrogen atom, an alkyl group, a halogenoalkyl group or an alkoxyphenylgroup with the proviso that R⁸ and R⁹ do no represent hydrogen atoms atthe same time and, when one of R⁸ and R⁹ is a halogenoalkyl group or analkoxyphenyl group, the other is a hydrogen atom, Ac represents anacetyl group, and Bz represents a benzoyl group; or a salt thereof.
 3. Adrug composition comprising the taxane derivative or the salt thereof asdefined in claim 1 and a pharmacologically acceptable carrier.
 4. Amethod the treatment of a tumor, which comprises administering thetaxane derivative or the salt thereof as defined in claim
 1. 5. The drugcomposition according to claim 3, which is an antitumor agent.